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6 NATIONAL HUMAN RESEARCH PROTECTIONS
7 ADVISORY COMMITTEE (NHRPAC) MEETING
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9 Tuesday, April 10, 2001
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1 A G E N D A
2 Tuesday, April 10, 2001
3 8:30-8:45 Brief Recap of Day One Questions/
4 Clarifications
5 Mary Faith Marshall, Ph.D.
6 8:45-9:00 The National Institutes of Health and
7 Human Subject Protections
8 Ruth Kirschstein, M.D.
9 Acting Director, National Institutes
10 of Health
11 9:00-12:00 Children
12 9:00-9:45 Discussion of Current Definitions and
13 their Interpretation
14 NHRPAC Committee
15 9:45-10:15 Update: Children's Workgroup
16 Alan Fleischman, M.D.
17 Senior Vice President, NY Academy of
18 Medicine, Clinical Professor of
19 Pediatrics and Clinical Professor of
20 Epidemiology & Social Medicine, Albert
21 Einstein College, New York
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1 10:15-10:30 BREAK
2 10:30-11:45 Committee Discussion
3 11:45-12:00 The National Science Foundation and
4 Human Subject Protections
5 Rita Colwell, Ph.D.
6 Director, National Science Foundation
7 12:00-1:30 LUNCH (On your own)
8 1:30-2:15 Update: Social Science and Discussion
9 Felice Levine, Ph.D.
10 Executive Officer
11 Philip Rubin, Ph.D.
12 Director, Division of Behavioral and
13 Cognitive Sciences
14 National Science Foundation
15 2:15-3:15 Public Comment
16 3:15-3:30 BREAK
17 3:30-4:15 Meeting Recap
18 Review Recommendations:
19 Financial Relationships
20 Declaration of Helsinki
21 Genetics
22 Family Members/Subjects
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1 Children
2 Social Science
3 Mary Faith Marshall, Ph.D.
4 4:15 THANK YOU - ADJOURN
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1 MARY FAITH MARSHALL, Ph.D., Chairperson, Director of Program
2 in Bioethics, University of Kansas Medical Center
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4 GREG KOSKI, Executive Secretary, Ph.D., M.D., Director,
5 Office of Human Research Protections, Office of Public
6 Health and Science, OS
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8 MARK BARNES, J.D., LL.M., Partner, Proskauer Rose LLP
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10 SANFORD CHODOSH, M.D.
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12 ELLIOT N. DORFF, Ph.D., Rector, Distinguished Professor of
13 Philosophy
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15 ALAN R. FLEISCHMAN, M.D., Senior Vice President, The New
16 York Academy of Medicine
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18 SUSAN Z. KORNETSKY, M.P.H., C.I.P., Director, Clinical
19 Research Compliance, Department of Clinical Investigation
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21 FELICE J. LEVINE, Phase.D., Executive Officer, American
22 Sociological Association
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1 ROBERT LEVINE, M.D., Professor of Medicine, Yale University
2 School of Medicine
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4 ABBEY S. MEYERS, President, National Organization for Rare
5 Disorders
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7 JONATHAN D. MORENO, Ph.D., Emily Davie and Joseph S.
8 Kornfeld Professor of Biomedical Ethics, Director, Center
9 for Biomedical Ethics, University of Virginia Health System
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11 MARY Z. PELIAS, Ph.D., J.D., Professor, Department of
12 Genetics, Louisiana State University Health Sciences Center
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14 ROBERT R. RICH, M.D., Executive Associate Dean of Research,
15 Emory University School of Medicine
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17 ADIL E. SHAMOO, Ph.D., Professor, Department of Biochemistry
18 and Molecular Biology, University of Maryland School of
19 Medicine
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21 JUDITH L. SIEGEL, Ph.D., Vice President, Head U.S. Clinical
22 Operations, Hoffman-La Roche, Inc.
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1 DENYSE THORNLEY-BROWN, M.D., Assistant Professor, Division
2 of Nephrology, University of Alabama at Birmingham
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4 KATE-LOUISE GOTTFRIED, J.D., M.S.P.H., Executive Director,
5 National Human Research Protections Advisory Committee
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1 P R O C E E D I N G S
2 [Time noted: 8:40 a.m.]
3 CHAIRPERSON MARSHALL: Good morning.
4 Welcome to the second day of our second meeting.
5 I would like to begin by thanking three
6 people who have helped make this meeting possible.
7 And they helped make the last meeting possible. They
8 keep me honest. Tony Goodwin and Carla Brown are
9 standing by the door. Thank you all.
10 [Applause.]
11 CHAIRPERSON MARSHALL: We've had, I think,
12 a spectacular meeting and we wouldn't have had it
13 without you. So thank you so much. We are very
14 grateful. And please convey my thanks and our thanks
15 to Barbara Smith too.
16 Thank you.
17 It's my honor to introduce to you -- I'm
18 sure you don't need an introduction -- Ruth
19 Kirschstein, who is the Acting Director of the
20 National Institutes of Health. And she is going to
21 open our meeting for us this morning.
22 DR. KIRSCHSTEIN: Good morning. I'm
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1 pleased to be here. I'm glad you invited me to come
2 and talk. I want to be sure that -- while I was here
3 for a few minutes at your last meeting, as I recall,
4 I didn't really say very much. And I wanted to be
5 sure that I would perhaps expand for you a little bit
6 on how NIH views what's going on and also how we are
7 approaching the activities.
8 There is no question that the protection
9 of the colleagues that we use as partners in the work
10 we do in clinical research is of utmost importance
11 and is the commitment that NIH has to these
12 individuals and to society and to the country as a
13 whole.
14 And, of course, it's been the focus, as
15 you know, of a number of policies that we have
16 thought about and worked on and have to some extent
17 are still evolving.
18 The philosophy behind those policies and
19 behind everything we do is that our concern about
20 these people must be as deep and as excellent as is
21 the science that we perform. We will settle for
22 nothing less.
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1 And the protection of these human
2 participants and the clinical trials are actually at
3 the heart of what we are doing. And we are concerned
4 and have been for a long time that we need to do more
5 clinical research. And we are searching, looking for
6 ways to increase the numbers of individuals that are
7 trained as physicians and other health care
8 professionals to enter the arena of clinical
9 research.
10 We have made enormous strides over the
11 last number of years in some basic discovery. There
12 is not a day that does not pass that in the
13 newspapers there are stories that hold -- if you just
14 listen to them and read them -- enormous promise.
15 But the promise can only be fulfilled if
16 we do clinical research that leads to conclusions
17 that can be verified, validated, and then moved on to
18 the next step. And that is only done if we have
19 highly qualified, highly trained, highly skilled
20 individuals who have the same sense that all of us
21 around this table have that when they are performing
22 clinical studies, they must be cognizant first and
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1 foremost that you do no harm to any patient.
2 And not only do we feel that way because
3 we ourselves believe it, but it's also because as
4 stewards of the public's money, we must assure that
5 those funds are used properly. And we have worked
6 very hard to do this all our lives. And it is no
7 accident, I think, but yesterday when the new budget
8 that President Bush proposed for NIH, the Secretary
9 of the Department of Health and Human Services, Tommy
10 Thompson, repeated, again and again and again at the
11 press conference, how much confidence he had that NIH
12 could spend this wonderful increase that the
13 president is proposing well with appropriate
14 safeguards in stewardship and would make new
15 discoveries that are going to be of very great
16 importance to people.
17 So we take this very, very seriously, not
18 just because we want him to say good things about us
19 continuously, but because we deeply feel this way and
20 this has been a commitment that I have had for the 45
21 years that I have been at NIH.
22 Now, in order to carry out these policies
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1 and procedures that we are putting in place, we want
2 them to be transparent to everyone that is concerned
3 so that there can be a smooth and transparent way of
4 carrying things out, yet an assurance that it is
5 being done correctly.
6 And we have to respect and operate within
7 the boundaries that define NIH, that define Dr.
8 Koski's position, that define practice because we are
9 not in the practice of medicine at NIH.
10 Now, in order to do that, we want to be
11 sure that our policies and our procedures are very
12 well understood by everybody and by our
13 investigators. We take great pains to put all the
14 material that we have in place in regard to
15 procedures and policies on the NIH web site. And
16 I've picked out some of the pages that you might like
17 and would suggest we hand them out to the members of
18 the committee. And for everybody else, you can reach
19 them and find them on the NIH web site.
20 In addition, we put out something called,
21 "The NIH Guide to Grants and Contracts" and that is
22 also on the web site. And in the web site on the
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1 front page, we have what we call a "Newsflash." So
2 anything new we do, you can find without any
3 difficulty at all by simply looking at the first
4 page.
5 We have recently put up new information on
6 human subjects and financial conflicts of interest
7 which lists and provides links to all the rest of
8 them.
9 Much of this is based on experience that
10 we have had recently when with the help of Dr.
11 Belinda Seto, who is here -- and actually she ran a
12 program on bioethics that we set up and we supported
13 a meeting that took place at Tuskegee about a year
14 and a half ago that those of you who are nodding
15 remember I was present at and spoke. And since then
16 we have had a number of a activities that we have
17 done. We have provided training grants for
18 bioethical activities as an example.
19 Now, one of the boundaries that everybody
20 has to understand, however, is that NIH is not a
21 regulatory agency. We do not have the regulatory
22 authority that allows certain things to take place so
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1 that we can basically take people to court. That is
2 the province of the Food and Drug Administration; it
3 is the province of other regulatory agencies. NIH is
4 primarily a research organization. So that our
5 activity comes from the moral sense of what we must
6 do and is looking at the stewardship of the federal
7 dollar.
8 But we don't and cannot demand that people
9 simply do something. We can persuade, we can use our
10 influence, we can do what we have recently done which
11 is to go out and look at what they're doing. We went
12 up to ten sites on what we call pro-active site
13 visits. That means that we have no notion. We don't
14 presuppose that anybody has done anything wrong.
15 We're simply going to take a look. And we have
16 completed those. We were very pleased with them and
17 the results of what went on are being also published
18 on the web site.
19 From them, of course, we learn. We learn
20 that not everybody does things the same way, and that
21 is the great thing about the NIH research system
22 because we can suggest then to one person, one group
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1 that perhaps having learned something from another
2 that it might be useful to use.
3 We can put policies in place. We can put
4 certain requirements in place, but we do not and
5 cannot demand.
6 On the other hand, if those policies are
7 not followed and there is no reason why that is not
8 so, and if this is a continuing process, we do have
9 the ability to terminate funds to that organization.
10 I also want to remind you that the funds
11 that we give for research grants are not given
12 directly to investigators. They are given to the
13 institution in which those scientists, those
14 clinicians, those clinical researchers work. And it
15 is the institution that has the ultimate
16 responsibility for that activity.
17 One of the things we have been working on
18 more recently is to make sure that the institutions
19 which clearly know they have the responsibility --
20 they certainly know it when they complain, when we do
21 something they don't like -- that they also know that
22 they have the responsibility to carry out the -- what
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1 we have charged them to do. And we are working very
2 hard on that aspect of things particularly in regard
3 to institutional conflicts of interest which is
4 something that we have not really, until maybe a year
5 or so ago, have not spent a lot of time considering.
6 The new realities of how institutions find
7 the funds which they need to do their work has made
8 it necessary for them to look at a broad array of
9 sources for funds and it's very important for them to
10 consider and for us to understand the conflicts of
11 interest that might occur.
12 We have, of course, in regard to clinical
13 trials and our oversight of clinical trials have had
14 a longstanding policy that in particular for Phase
15 III trials demands that there be -- and I use the
16 word "demand," that's probably not right -- asks that
17 there be data in safety monitoring boards. And that
18 policy has been generally acceded to because I think
19 it has -- it is general practice that when you are
20 doing very large trials you must be sure that there
21 is a group that can look at the data in an objective
22 way.
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1 But we recently have decided we need to do
2 some more monitoring on both Phase I and Phase II
3 clinical trials. And so we now ask applicants to
4 submit to the NIH for review and approval a
5 monitoring plan that includes the mechanisms for
6 recording any adverse events.
7 This is still not regulatory, but it is
8 what we expect. Now, there is one place where
9 clearly these move together. And that is that any
10 NIH-supported investigator who is doing the clinical
11 work in a Phase I or a Phase II or even in a Phase II
12 clinical trial under an investigational new drug
13 application approval from the Food and Drug
14 Administration must follow those regulatory
15 requirements and we will watch for that as well.
16 One of the things that is very important
17 in this process of dialogue is communication is
18 between all concerned. We have scientists who are
19 administrators who monitor/oversee what is going on
20 in the research grants and even more so in research
21 contracts and a number of clinical trials,
22 particularly Phase III would be done under a research
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1 contract mechanism rather than a research grant
2 mechanism. Not all. We leave that to the discretion
3 of the investigators.
4 But we must have dialogue between these
5 people and watch what they're doing and watch what
6 the institutional review boards do. And so we
7 require them to inform us of anything that they are
8 doing for which the Food and Drug Administration has
9 jurisdictional authority. And we therefore learn
10 from what they are holding.
11 An investigator has received a letter from
12 the Food and Drug Administration on some particular
13 aspect of the trial we ask them to share that with
14 us. I must say that until recently that was not
15 something we did and it turned out to be unfortunate
16 and we are now increasing that and making that
17 happen. This is a mechanism for improving oversight.
18 We are evolving just as everyone else is.
19 We think that the knowledge of ethics and
20 research integrity is fundamental to good clinical
21 practice. We require that the trainees who are on
22 our training grants to do research, basic research
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1 primarily take some sort of training in research
2 integrity and we are hoping that people also have
3 such when they're doing clinical work and we're
4 devising some new ways to do this and we are going to
5 require that these be done.
6 We have this bioethics training grant
7 support which is called a T-15. We have made a
8 number of awards and we would be delighted to have
9 more individuals, more institutions have that.
10 So let me summarize by saying that I think
11 that our approach is based on our notion of
12 objectivity in research. Financial conflicts of
13 interest, but those aren't the only ones, we require
14 the institutions to have written enforced policies on
15 that. And they are required to report to us to
16 manage, reduce, and possibly eliminate those. But we
17 are evolving and we are working on a number of
18 concerns and therefore we need to go further. And I
19 think I'll stop and answer any questions.
20 CHAIRPERSON MARSHALL: Thank you, Ruth.
21 I just would like to make a comment before
22 we entertain questions. And that is that we have
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1 four of your colleagues at the NIH who work very
2 closely with us on our committee, Alan Sandler,
3 Belinda Seto, Hillman Grave and Judith Wayland.
4 I had the opportunity recently at an
5 Institute of Medicine meeting -- that's looking at
6 assessing the systems of protecting human subjects of
7 research -- of hearing a presentation by Belinda
8 giving us an overview of the efforts that the NIH is
9 making. And I commend you highly. I think that
10 especially in the area of monitoring and your new
11 requirements for some sort of monitoring, not only
12 for Phase III, but for Phase II and II trials is
13 helping to change the paradigm of how research
14 protections are unfolding in this country and the
15 educational efforts that you are making and that you
16 are requiring are wonderful. The presentation was
17 very impressive. So I thank you.
18 DR. KIRSCHSTEIN: I thank you on Belinda's
19 behalf.
20 CHAIRPERSON MARSHALL: And I just would
21 like to say to you that we are working with your
22 colleagues and we are delighted to have them as very
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1 important members of this group and also to let you
2 know that we are at your service in any way. So we
3 hope that you will ask us in the future --
4 DR. KIRSCHSTEIN: Sure.
5 CHAIRPERSON MARSHALL: -- if we can ever
6 do anything for you.
7 And let me just ask committee members, ex
8 officio members, or members of the public if you have
9 questions? Abbey and then Jonathan.
10 MS. MEYERS: Yes. One of the repeated
11 things that we are hearing are complaints by IRBs
12 that they don't have the resources to do everything
13 now that all of this is happening. Is there any way
14 that they could put as an indirect cost some of the
15 costs for the IRBs.
16 DR. KIRSCHSTEIN: We are fully aware of
17 that and we are looking into it. It is not an easily
18 solved problem. One doesn't want to interfere with
19 the institutional responsibilities. The indirect
20 costs are set by OMB and so forth. But we are
21 looking into ways in which this might be done. We
22 are very much aware of the problem and we're trying
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1 to look into it. There are a number of problems
2 we're aware of and there are a number of things we
3 need better coordination within NIH and some other
4 things. I've been talking to many people about it.
5 I see Bob Wood is sitting -- standing --
6 excuse me -- in the back and he's been enormously
7 helpful to me on clinical trials. I spend a lot of
8 time thinking about this, so we're working on it.
9 CHAIRPERSON MARSHALL: Jonathan.
10 DR. MORENO: I've also experienced the
11 energy with which the institutes are focusing on the
12 DSMB role. I've gotten a lot more calls about being
13 on DSMBs in the last few months than ever before.
14 And they're about as lucrative as serving on NRPAC,
15 by the way.
16 [Laughter.]
17 DR. MORENO: But we do them because they
18 are important. And I'm wondering if you could say a
19 little bit more -- somebody could day a little bit
20 more about how the institutes decide when to generate
21 DSMB, if there are some criteria besides the size and
22 complexity that are intuitive about a trial.
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1 DR. KIRSCHSTEIN: I'm not an expert and
2 maybe Bob can tell us that or somebody else. But I
3 can tell you what I think. And actually, when I said
4 to you that NIH is not a regulatory agency, those of
5 you who know NIH used to have as part of its
6 structure a regulatory agency called the Division of
7 Biological Standards which was related to vaccine
8 controls. I worked for that agency for 19 years, so
9 I know a lot of -- and then it was transferred to
10 Food and Drug Administration, so I know a lot about
11 regulatory policy.
12 It is the complexity primarily and the
13 size. It is probably also if it's the first large
14 trial of the sort that's being done, if it is using a
15 drug or a vaccine or an intervention that is unique,
16 has never been tried before, all of those things
17 would go into it. But this is why we have a group of
18 what we call health scientist administrators who are
19 physicians, nurses, other people who are very much
20 aware -- statisticians -- who are very much aware of
21 the needs of clinical trials, the needs of the
22 patients to come together with a leader who has been
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1 involved in clinical trials for years.
2 Dr. Wittis is a clear example of that, who
3 together decide even before they think about putting
4 out any sort of request for such a trial or before
5 the trial has been more than a gleam in somebody's
6 eye, whether or not among the parameters will be the
7 need for a data safety and monitoring board. When
8 there are very big trials, very often they have a
9 coordinating center which is separate from when it's
10 a multi-institutional trial the one I will bring to
11 mind is the one I know most about which is the
12 women's health initiative which is done in something
13 like 44 institutions throughout the country. There
14 is a coordinating center which is in an institution
15 that is not doing part of the trial, but the data
16 come into that organization and the people are
17 supported under the grant to analyze the data as it
18 comes, look at it, determine whether there are things
19 that would make them want to have a DSMB look at
20 something earlier and that supports the DSMB. So
21 there are a number of factors.
22 Bob, would you want to add anything?
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1 DR. WOOD: Speaking only for the Cancer
2 Institute, our stipulation for DSMBs as opposed to
3 simply a DSM process which might or might not be a
4 DSMB is really reserved for Phase III. And we don't
5 have any -- we're in the process of drawing up some
6 guidance now for our investigator community about
7 what the essential elements of the DSM plan should be
8 for trials other than Phase III.
9 We have no present plans to mandate the
10 use of boards as such. Though my own view is that
11 for trials of sufficient size and complexity and
12 where there's a real chance or where there is some
13 reasonable chance that one might want to make early
14 stopping decisions that are best made on the basis of
15 blinded data, investigators would be wise to consider
16 a formal separate board.
17 The only other thing that I would remind
18 you of is that the DSM plans are actually peer
19 reviewed now on all grants that come in. So in
20 addition to MCI wishes, peer reviewers have a chance
21 to get in on the act too.
22 CHAIRPERSON MARSHALL: Thank you. Bob
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1 Levine. And one last question. Sorry.
2 DR. R. LEVINE: I just wanted to say that
3 the DSMBs at NIH are there's a great variety of
4 missions and structures. I'm on, I think, four or
5 five of NIH's now.
6 I find that some of them have
7 responsibility for reviewing all research of a
8 certain type that's done within the Institute. I've
9 seen that in NIMH and in NIAID. While some seem to
10 have one DSMB for each particular trial, I've seen
11 that model in Heart, Lung, and Blood and in the Eye
12 Institute.
13 I think one of the great problems that
14 needs resolution is an official statement on the
15 extent to which the DSMBs can be expected or required
16 to share their findings with the IRBs. There's a
17 remarkable diversity of opinion being expressed. I
18 have my own opinion, but I would like to hear yours.
19 [Laughter.]
20 DR. KIRSCHSTEIN: I think I'll take that
21 under advisement. I'm writing down the note to talk
22 to several institute directors and so forth about
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1 this. I might say that I think that the difference
2 that you're characterizing between National Institute
3 of Allergy and Infectious Diseases perhaps the Heart
4 Institute is that probably the DSMB that you're
5 thinking about in NIAID is related to a clinical
6 trials network that's working on a particular --
7 particularly the AIDS network as opposed to the Heart
8 Institute doing -- having this for Phase III trials
9 individually.
10 I'll take one more.
11 CHAIRPERSON MARSHALL: Elliot. Welcome.
12 DR. DORFF: Thank you. Appreciate it.
13 Moral behavior in society is in part a
14 function of regulations, but it's much more a
15 function of education. I was very much interested in
16 your educational efforts and the extent to which
17 those could be modeled and other kinds of protocols.
18 DR. KIRSCHSTEIN: What kinds of protocols?
19 DR. DORFF: Well, what I have in mind is
20 that -- I mean, if you're doing the kind of thing for
21 educating researchers that we might recommend to
22 everybody doing research, then I would like to hear
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1 about that. In other words, what kind of -- I'm
2 looking for curricula. I'm looking for amount of
3 time you spend and what kinds of topics you do. In
4 other words, the kind of educational analysis that
5 would go on in any program just to find out whether
6 this might be a model for us to recommend to other
7 people doing research.
8 DR. KIRSCHSTEIN: I think you can get
9 those details primarily for the kinds of training
10 we're planning for these activities from Dr. Seto.
11 But, in addition, the Office of Research Integrity
12 has a group of educational activities that it is
13 planning in regard to teaching Ph.D. candidates,
14 particularly, but also any other candidates, under
15 training to do research that might be -- that is
16 supported by NIH in general about what it means to be
17 a good and honest and true scientist. And I think
18 you can get it from them.
19 Chris Pascal would be the person to get
20 that from.
21 CHAIRPERSON MARSHALL: Thank you very
22 much.
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1 I want to just update the folks who
2 weren't here yesterday and Elliot welcome. We are so
3 glad that you're here. We know that you have been
4 working hard because we heard that from Mark Barnes
5 yesterday.
6 Yesterday for those of you who weren't
7 here, we had three primary things on our agenda. We
8 had a report from the financial relationships group
9 that was chaired by Mark Barnes. And the members of
10 the committee who helped Mark are Judy Siegel, Sandy
11 Chodosh, Adil Shamoo, Elliot Dorff, and Kate
12 Gottfried, as always, was a steadfast member and
13 supporter of their work.
14 And I want to say that I made some remarks
15 at our first meeting at the opening session and I
16 exhorted the Committee to help us raise the roofbeam
17 high. And those lawyers can tend to take things
18 literally and damned if Mark Barnes didn't do it. I
19 think he's put us through the roof. He certainly
20 raised the bar very high for those who are going to
21 follow after him as workgroup chairs. So, thank you,
22 Mark and Committee members. You all just did a
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1 stellar job.
2 My sense of where we are with the
3 financial relationships draft report on the draft
4 interim guidance is that we will do this: we will
5 post on our web site the draft report from the
6 working group. We will ask for comments from the
7 public, for our ex officio members, from any members
8 of the committee who didn't have time or sufficient
9 opportunity to weigh in on the draft report, the
10 committee will convene again; take all of that
11 feedback into consideration, and give us an
12 penultimate draft which we will then ask -- I am
13 going to ask committee members, you all have a
14 mechanism for reviewing materials and commenting on
15 them via our network, our Internet, capabilities as a
16 committee, so I'm going to ask you to do that prior
17 to the next meeting -- our next meeting in July --
18 when I hope that Mark can then present the 30th and
19 31st of July when Mark can present something to the
20 committee that we feel that we as a committee are
21 ready to move forward with and to endorse.
22 So I'm putting the onus on you committee
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1 members, please, to get your feedback to Mark prior
2 -- on both of those occasions -- prior to the
3 revision of the draft and then once afterwards so
4 that we can move forward with that at our next
5 meeting.
6 Thank you, Mark, very much, and the
7 members of your group for a stellar job.
8 And I'm going to ask Mary Kay to just give
9 us a brief recap of -- she is going to chair our
10 genetics workgroup of what we agreed to yesterday and
11 let the committee know how we are going to proceed in
12 that area.
13 DR. PELIAS: We've assembled an impressive
14 group of people who have agreed -- more or less most
15 of them have completely agreed and some are a little
16 bit reserved to work with us on this committee.
17 Margaret Borwhat, Denise Thornley-Brown, Abbey
18 Meyers, Sandy Chodosh, Jonathan Moreno, Terri
19 Sergeant, Felice Levine, and I'm hoping that I will
20 be able to call on a couple of consultants, perhaps
21 Doug Levinson and Jeff Botkin, both of whom were here
22 yesterday offering their ideas about human subjects
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1 and others as -- I'm new to this, so I don't know how
2 many people I'm supposed to involve and so on, but
3 we'll work on it.
4 Also, we're supposed to include the ex
5 officio members of the committee. At any rate we see
6 the charge for the working group. First of all,
7 there are several topics, but the first and foremost
8 topic will be defining a human subject. We intend to
9 gather definitions that have been incorporated into
10 the common rule and see if we can find any common
11 ground in the common rule for definitions of humans
12 subjects. And we'll try to figure out whether or not
13 we can synthesize a single definition, certainly one
14 that is broader than genetics which is where my own
15 personal interest is. But we'll work outside of
16 genetics for quite a while.
17 The second question in relation to human
18 subjects is to try to determine when a family member
19 becomes a research subject from whom we must obtain
20 consent and if we have to obtain consent, how should
21 we go about doing it. So this is our primary
22 interest for at least the next couple of months. And
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1 then as we were discussing this last night, I think
2 we agreed that we might continue along with the list
3 that Francis Collins presented to us yesterday in
4 solving issues having to do with genetics, the next
5 one being the need for community consultation if risk
6 of stigma goes beyond the individual. This is
7 something that has been addressed on occasion, but I
8 don't know that it's ever been addressed formally.
9 The next topic might be research with
10 stored tissue samples, and the next one, the question
11 of blanket consent for future use, both of which go
12 to one of my favorite words, and that is to
13 "anonymize."
14 And the last topic that we might get to
15 one of these days has to do with disclosure of
16 research results, results that are generated in
17 research laboratories, whether or not we should do
18 something with intermediate results that have not
19 been confirmed and are not clearly approved. Whether
20 they have significant implications for a subject's
21 health or a family's health. Whether we are going to
22 get involved in questions of law and malpractice, and
431
1 whether we have a duty to provide care and
2 counseling.
3 But, first of all, we could spend the rest
4 of our lives doing all of these topics, I think. But
5 first we will try to define a human subject, and that
6 will take a great deal of energy and cooperation.
7 That's is.
8 CHAIRPERSON MARSHALL: Thank you very
9 much, Mary Kay. Those fundamental definitions and
10 assumptions are really important and they are truly
11 the hardest work. So thank you for taking on that
12 challenge.
13 Our agenda today involves and update, a
14 report from the Children's workgroup. Alan
15 Fleischman has, as you all know, reported to our
16 group. He actually got us going at our first
17 material and helped us define the issues that we
18 should be pursuing and then like any wise committee
19 we decided that we would invite him to help us do
20 that. So we are delighted that he is now a member of
21 our committee and chairing the workgroup. And I am
22 going to turn the floor over to Alan. And, yes, we
432
1 will switch places, Alan. So, thank you.
2 DR. FLEISCHMAN: Thank you. I want to
3 start by saying that we had a stellar children's
4 workgroup. Although we've only had one moment in
5 time when we were either in a room or on a telephone
6 together and this is clearly a work in progress.
7 Even the children's workgroup have not had adequate
8 time to comment on the draft that is before you
9 today.
10 What I would like to do today is to first
11 tell you about the group; second tell you a little
12 bit about children's regulations and Subpart D so
13 that we're all at the same place, and walk through
14 the workgroup report which has 21 areas of interest,
15 but only talk about four of those which I think are
16 the most important issues to raise for conversation.
17 And I would like to raise each of those individually
18 for conversation.
19 The workgroup included several members of
20 the committee. Susan Kornetsky, Felice Levine, Mary
21 Faith Marshall, and Kate Louis Gottfried was both a
22 participant and staff support. I want to say that we
433
1 are indebted to Ms. Gottfried who has really been
2 more than a stalwart, but a tremendous contributor to
3 this process. And I would like to say publicly that
4 as an ethics group, 22 hours a day, seven days a week
5 seems like more than even we could expect from an
6 employee of either a public or private institution.
7 But we are receiving that kind of support.
8 There were outside members as well of this
9 group; John Abramson, Myron Genel, Christine Gleason,
10 and Skip Nelson from the Pediatric Research Community
11 and Academic IRBs within the Children's World.
12 Gilman Grave represented by Judith Whalen from the
13 NIH; Suzanne Roberts from the FDA; Don Rosenstein
14 from the NIMH who chairs their IRB and has mental
15 health interests; Susan Winer who is an advocate as
16 the parent of a child who has had a serious illness
17 and died; and I think that covers it.
18 Now, some of these folks were only at the
19 meeting by telephone. But I want to give credit to
20 them for that hard work. We will also add to the
21 group Jonathan Moreno from the committee and James
22 Lechman and Robert Murray as we go forward with this
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1 work.
2 The charge to the committee was not to
3 look at everything about children's research, but to
4 primarily look at both Subpart D and some specific
5 questions that were asked of the Secretary of Health
6 and Human Services to respond through the October
7 2000 Public Health Service Act. And there were ten
8 questions and we did try to at least address in some
9 level all of those ten questions at the request of
10 Dr. Koski and others in Health and Human Services.
11 Now, let me remind you that Subpart D --
12 CHAIRPERSON MARSHALL: He's a true medical
13 humanist, he's not using slides.
14 DR. FLEISCHMAN: We're going to go low
15 tech today because I want to walk through some of
16 these things and I think we will be better able to
17 have a dialogue.
18 Subpart D reminds us that there are four
19 levels of permissible research in these regulations.
20 The first has to do with minimal risk research which
21 is permissible in children. And we've heard that
22 definition many times reminding you that in the
435
1 definitions "minimal risk" means that the probability
2 and magnitude of harm or discomfort anticipated in
3 the research are not greater in and of themselves
4 than those ordinarily encountered in daily life or
5 during the performance of routine physical or
6 psychological examinations or tests. The workgroup
7 has some comments about that that we'll get to in a
8 moment.
9 The second permissible risk is those --
10 and permissible research is research that has the
11 prospect of direct benefit to the individual child.
12 The third --
13 DR. R. LEVINE: Alan, I want to comment on
14 that. What you've done is you've read the subtitle.
15 The subtitle is not related to the text of the
16 regulation. The text of the regulation never says
17 that research holds out a prospect of direct benefit.
18 It says that research -- or it is concerned with, and
19 I quote, "Interventions or procedures that hold out
20 the prospect of direct benefit." And it's only those
21 interventions or procedures that the level of risk as
22 a threshold standard is related to.
436
1 Thank you.
2 DR. FLEISCHMAN: The third permissible
3 research has to do with research involving greater
4 than minimal risk, no prospect of direct benefit to
5 individual subjects, but likely to yield
6 generalizable knowledge about the subject's disorder
7 or condition. And the committee has some thoughts
8 about that level as well.
9 And then, finally, the 407 section tells
10 us that research not otherwise approvable which
11 presents an opportunity to understand, prevent, or
12 alleviate a serious problem affecting the health or
13 welfare of children can be approved through a federal
14 process at the level of the Secretary. And we'll
15 comment on that.
16 Section 408 of Subpart D speaks to the
17 requirements for permission and assent of children
18 and the ability to waive those in certain
19 circumstances.
20 The workgroup -- and I'm going to turn to
21 its draft 4501 document. The workgroup took it's
22 charge seriously and attempted in its single meeting
437
1 to at least address each of the areas of concern.
2 There were four general impressions that the
3 workgroup had about regulation of research in
4 children.
5 The first was that to this group of
6 investigators, ethicists, and advocates, the existing
7 regulation seemed to be sound, have worked, and are
8 in need of clarification in order to enhance the
9 uniform use of the regulations.
10 Second, that the workgroup believes that
11 the investigators who do research in children and the
12 IRBs that review and monitor research in children
13 must be adequate to the task.
14 And that I think is an important question
15 that needs to be raised about what constitutes an IRB
16 able and competent to do review of children's
17 research. And as part of that, there was concern
18 that there be adequate representation among the
19 community members of people who actually,
20 unaffiliated with the research, have the community
21 standard and understanding of children's issues and
22 advocacy for children's interests.
438
1 Fourth, the workgroup believes that the
2 regulations are applicable to social science
3 research, but require further clarification in that
4 regard and we're going to leave that primarily to our
5 social science research working group which we'll
6 hear about more later in the day.
7 There is some concern about clarification
8 in this area, understanding by IRBs of exempt and
9 expedited work as well as the importance of
10 confidentiality and privacy in social science
11 research.
12 Now, let me focus on four major issues.
13 As I say, the workgroup commented on 21 areas, but
14 four of which we want to focus your attention on for
15 conversation. And I think, Madam Chairperson, that I
16 would take one at a time and then ask for comment if
17 that's okay.
18 CHAIRPERSON MARSHALL: That's fine. The
19 floor is yours and this is your session.
20 DR. FLEISCHMAN: The first question asked
21 was the appropriateness of the regulations for
22 children of differing ages and maturity levels
439
1 including legal status. Which raises one of, I
2 think, the important questions that need
3 clarification concerning adolescent assent and
4 concent.
5 We know that legally emancipated minors
6 may be treated as adults in terms of research, but
7 that's a small group of adolescents. There are,
8 however, a group of adolescents who are felt to be
9 what has been called "mature minors." That is,
10 adolescents who have at capacity to assess risks and
11 benefits and understand their interests and have the
12 ability to think longitudinally about consequences.
13 There are also adolescents who in
14 virtually every state are allowed to concent for
15 clinical care around certain specific diseases.
16 Primarily sexually transmitted diseases, pregnancy
17 care, things of that sort. And although the National
18 Commission had recommended originally that those
19 children who are allowed to legally consent to
20 clinical care ought to be allowed to consent for
21 research in those areas.
22 That did not transpose word-for-word into
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1 the present regulations. So there is still some
2 concern and confusion among the IRBs as well as the
3 investigators concerning what may we allow
4 adolescents to consent to without involving parents?
5 What level of assent is involved in such work when
6 parents are giving permission? And the workgroup
7 does believe that there are times when it might not
8 be in the interests of the adolescent to inform the
9 parent about an illness or behavior which is under
10 study.
11 That the IRB presently, through Section
12 408, has the authority to waive parental permission
13 in such cases when the IRB creates an adequate
14 process for the protection of the adolescent. Which
15 generally will include processes which will have
16 separate independent advisors or counselors for the
17 adolescent as well as monitoring of the consent
18 process.
19 The question as to how much work needs to
20 be done in determining that the adolescent has the
21 capacity to make these judgments and whether in every
22 case an adolescent would need to have such an
441
1 assessment or whether the capacity determination
2 ought to be tied to the level of risk; and if it were
3 minimal risk there would be an assumption of capacity
4 versus higher levels of risk would require more
5 involvement of independent assessments of capacity.
6 These are things that need some
7 clarification and we believe ought to -- let me just
8 finish the presentation and we'll then open it for
9 conversation -- we believe ought to be within the
10 purview of the IRB as presently allowed in Section
11 408, but requires clarification so that the IRBs will
12 be using this in a uniform manner with examples and
13 clarity of suggestion.
14 So let me pause here and take some
15 comments or questions about just this issue now, the
16 adolescent assent/consent issue. Abbey?
17 MS. MEYERS: Excuse me, but I have to step
18 backwards a bit because there are some assumptions
19 that you're asking us to accept before. First of
20 all, I want to raise the question about the
21 composition of this committee because it seems that
22 there are very few members of this committee on your
442
1 workgroup and most of the members are not from the
2 committee. And I don't think we've really determined
3 what the composition of workgroups should be.
4 Because, you know, if I was going to try to pass a
5 recommendation on the oil business, I'm not sure
6 whether, you know, a gas station owner should be the
7 members of the committee. I think we really need to
8 examine that.
9 Secondly, you're asking us to accept your
10 basic theory that the current system is just fine, it
11 needs a little bit of clarification. And I can't
12 accept that. I don't think that the current system
13 is adequate in today's world, especially when we have
14 commercial companies out there soliciting children
15 with Toys-R-Us coupons to come in and participate.
16 So that's just a basic thing I wanted to say before
17 we focus in on the adolescent thing.
18 DR. FLEISCHMAN: If I can just comment on
19 the workgroup composition. There are six members of
20 this committee and there are only 17 -- well, five
21 members of the committee and the staff executive on
22 this workgroup. We did ask, as was suggested in the
443
1 actual Public Health Act, we asked experts in
2 children's issues --
3 MS. MEYERS: There are 11 outsiders from
4 what I counted and there's five members of the
5 committee. So I think that the ratio there is not
6 quite right.
7 DR. FLEISCHMAN: Well, we actually do have
8 the FDA and the NIH representatives who are liaison
9 to the committee. I guess we could call those
10 outsiders. But I didn't consider them that way. We
11 also asked people who have different knowledge bases
12 in children's issues, realizing that children go from
13 the one-pound premature to the 300-pound line backer,
14 it is a very broad research base with different kinds
15 of expertise both in the biomedical as well as in the
16 psychosocial areas.
17 I will say, though, that none of the
18 committee members were shy or reticent and to my
19 knowledge none -- and they can speak for themselves
20 -- non dramatically disagreed with this report yet.
21 It may well be that in their second or third reading
22 they have things to tell us about it.
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1 To comment about the general issue that
2 you raise, we do actually talk about incentives in
3 this report. We make some specific recommendations
4 about the incentives and I would very much, Abbey,
5 ask you to focus on the regulations when you ask if
6 something needs reassessing or rewriting.
7 It may well be that we need to rewrite
8 these regulations. But in my opinion we need not to
9 rewrite the regulations in order to take care of the
10 problem you address which is a very serious question
11 about recruitment and incentives which the workgroup
12 is interested in and comments on.
13 So the question that we need to think
14 about is whether the structure of the definitions as
15 well as the permissible levels of research are flawed
16 or need such overwork or such redoing that we need to
17 rewrite the regulations and we may well need to do
18 that. I don't believe we do. But we may have to do
19 that.
20 We started the workgroup by asking that
21 question and there were no members of the workgroup;
22 and correct me if I'm wrong, there were no members of
445
1 the workgroup present or on the phone who believed
2 that the regulations required rewriting.
3 Susan.
4 MS. KORNETSKY: Abbey, I would just like
5 to add that I fully agree with what's been said, and
6 I also see your concern. I think before we sort of
7 jump to rewriting the regulations, I agree, there
8 probably have been some misuses of interpretation of
9 the regulations and I think that's what we are trying
10 to sort out. Whether it's that there's guidance
11 needed and how they are intended to be applied, or
12 whether the regulations per se, are just -- you know,
13 are not workable. And I think we are starting with
14 the context that the regulations may be workable. We
15 have a lot of work to do to educate and then people
16 and guidance in working within the regulations.
17 DR. FLEISCHMAN: Kate.
18 DR. GOTTFRIED: I just also wanted to
19 mention that the financial relationships workgroup
20 was composed of five members of the committee and
21 this is a similar situation. And what was felt was
22 that in order to get information to provide to the
446
1 NHRPAC as a whole, we needed some greater expertise
2 in the area.
3 Mary Faith herself is an expert in
4 children in prisoners, but we needed people who
5 really work in the area of children's research to get
6 better informed in order to make an assessment with
7 respect to the regulation and whether it might
8 require revision.
9 MS. MEYERS: Shouldn't there be some kind
10 of ratio? I mean, was the four or five members on
11 the financial relationship thing, was it 11 non-
12 members.
13 MS. GOTTFRIED: The workgroup process has
14 evolved to recognize that we need as broad input as
15 possible. With respect to the financial
16 relationships instance, we had already had a document
17 that they were specifically reacting to. In this
18 particular instance, we knew that there were also
19 specific areas to focus on and that we needed a
20 certain amount of expertise. We asked for volunteers
21 from all over the committee, the NHRPAC committee and
22 as you know everyone is spread very thinly. So there
447
1 is only a certain amount of workgroups that each
2 committee member can sit on.
3 DR. FLEISCHMAN: I have a list of people
4 in order of recognition, Felice, Adil, Bob and Mark.
5 And we will continue to use this methodology.
6 Jonathan is on the list. Felice?
7 DR. F. LEVINE: I also wanted to
8 underscore, I think, what Susan said and as the co-
9 chair of the social and behavioral science working
10 group, I can see this as a bit of a theme which is
11 the issue I addressed in December and that is that
12 the rules often are not, per se, the problem. But
13 it's that gap between the language and the
14 implementation.
15 Now, it may be that the recurrent
16 identification of gaps become such a preponderant
17 fault that the language itself needs to be clarified.
18 But I have felt from the outset, both in this group
19 and on that conference call, and on my conversations
20 with Mary Faith that ultimately addressing the common
21 rules and where they may need clarification,
22 expansion, or transformation, as we discussed
448
1 yesterday is well within the scope of what we might
2 do. But nothing jumped up so powerfully that we
3 thought that needed to be addressed before we really
4 analytically understood the applications and the
5 problems. And I think that's what Alan is trying to
6 speak to.
7 DR. FLEISCHMAN: Adil?
8 DR. SHAMOO: This question is really to
9 Kate and Mary Faith and that is in concordance with
10 Abbey's remarks we as a committee -- I personally,
11 for one, I don't know how the workgroups were
12 formulated, why members were there. They never
13 brought the membership back to this committee to sort
14 of give them the nod; usually we will say yes. I'm
15 just -- in the process that's one.
16 Second is that the workgroups are weeding
17 out -- and I said to Mark, "I won't bring it up."
18 But I'm glad Abbey brought it and induced me to say
19 that -- and that is, these workgroups are really
20 functioning as subcommittees. They are bringing
21 well-written drafts with recommendations with
22 specifics and the process is not transparent. I
449
1 would like to see -- one of my frustrations was, one
2 reason I had my own statement on financial
3 relationships is what was said during the working
4 group despite the fact that I think Mark did a
5 brilliant job and a stellar, but nevertheless was a
6 summary of what went on.
7 The public at large doesn't know those
8 deliberations and I want people to be on record what
9 they are saying rather than only confidentially they
10 are talking about it. And I think we need to clarify
11 the process by the chair before we proceed.
12 CHAIRPERSON MARSHALL: Thank you, Adil.
13 You are raising some housekeeping issues, you and
14 Abbey both. And I will attend to those now.
15 My promise and goal is that everything
16 that we do will be transparent. We are finding our
17 way. I am delighted that Terri Seargent who was here
18 yesterday has, at my request, joined the workgroup on
19 genetics and Doug Levinson as well. And I made an
20 appeal yesterday to any member, public member, ex
21 officio member, or member of the committee who would
22 like to serve on the workgroup to let us know. So,
450
1 my plan is for there to be an open invitation for
2 participation on the workgroups.
3 And, again, Adil, we are finding our way.
4 So I think that the process that we set up, for
5 example, with the financial relationships workgroup,
6 we cannot sort of craft documents as a committee.
7 That's not an efficient use of our time. So there
8 has to be a mechanism for something to be brought
9 back to the committee as a whole. So I hope that the
10 workgroups are not functioning as subcommittees.
11 They can't.
12 So the process of having this document put
13 up on the web as a draft for input from any and
14 everyone, I think is our mechanism for involvement.
15 And I truly do mean that. So I am encouraging the
16 members of the committee who are on our list serve,
17 even though they may not and can't sit on every
18 workgroup, they have an opportunity to participate in
19 the creation and the drafting of these documents as
20 the process moves along.
21 So what was presented yesterday was by no
22 means a fait accompli, nor was it intended to be. So
451
1 now it will be on the web site. It is open for
2 comment and input from anyone. And I truly mean
3 that.
4 So if you have other suggestions in terms
5 of how workgroups should proceed, I would welcome
6 them. Let me just finish. Because I very much do
7 want us to be transparent. We have to be by our
8 charge, and morally in terms of what we're about.
9 So let me know if you have thoughts in
10 terms of the mechanisms.
11 Now, I hear what Abbey is saying is a
12 concern that I second. Abbey, the participation,
13 meaningful participation, of the public or of persons
14 who are advocates for research subjects is near and
15 dear to my heart. So, again, there is an open
16 invitation from the Committee, perhaps we need to be
17 more thoughtful in terms of appointing people. So
18 your concern is about ratio and numbers. And I hear
19 you. So as a committee, then let us be committed to
20 that, in forming workgroups as we move along.
21 MS. MEYERS: My concern is that, we
22 shouldn't put together a group of people who are
452
1 regulated by the regulations and then say to them, do
2 you want to be more regulated? Do you think these
3 regulations are sufficient? I think it should be
4 people who don't make their living in research who
5 are the majority of that committee.
6 DR. FLEISCHMAN: I've got a hold to the
7 list and hope that we can continue on this. Bob, are
8 we talking about the topic that Mary Faith has just
9 spoken to, or are we moving back toward adolescence?
10 Let's stay with Mary Faith's conversation for a few
11 moments.
12 DR. R. LEVINE: I want to speak to Mary
13 Faith's statement, but I don't want to lose my place
14 in the queue --
15 [Laughter.]
16 DR. R. LEVINE: -- that caused me to raise
17 my hand in the first place.
18 CHAIRPERSON MARSHALL: Let me just also
19 say that I think that we have got some room in our
20 schedule today where we might carve out some time to
21 talk about these housekeeping details because they
22 are very important. So let's go back to the children
453
1 and then at the end of the day, let's do talk about
2 these.
3 DR. R. LEVINE: Meanwhile, back at the
4 children.
5 DR. FLEISCHMAN: Okay. Robert.
6 We're going to go back to the children and
7 on my list at the moment are Bob, Mark, and Jonathan
8 and we're talking specifically about the adolescent
9 consent/assent issue.
10 DR. R. LEVINE: I want to begin by saying
11 that it's very important that everyone who
12 participates in this discussion recognize that the
13 language of the regulations is very important. There
14 is no such thing as beneficial research. The
15 subtitles -- well, when the National Commission
16 issued its report and recommendations on research
17 involving children, it said flatly, there is no such
18 thing as beneficial research and that you must
19 instead be looking at each component of the research
20 to see whether or not it holds out the prospect of
21 direct benefit.
22 The danger of talking about beneficial
454
1 research is that you get into what I call the fallacy
2 of the package deal. If one thing looks a little
3 beneficial, then everything is approved according to
4 standards designed to be more permissive for
5 beneficial procedures, not research.
6 When the regulation writers then issued
7 proposed regulations that referred to beneficial
8 research, the National Commission intervened and
9 said, no, you just didn't get it so that the
10 regulation writers then wrote what we now have on the
11 table in front of us, that procedures or intervention
12 either do or do not hold out the prospect of direct
13 benefit. At that point the National Commission went
14 out of business and the regulation writers wrote
15 subtitles that had nothing to do with the texts and
16 these have polluted commentary on these regulations
17 ever since; that people keep talking about 405
18 research involving greater than minimal risk by
19 presenting the prospect of direct benefit.
20 And I think it's very important. It took
21 20 years to get the concept of beneficial research
22 out of the regulations. The final step was to
455
1 rewrite the Subpart B for research involving the
2 fetus and pregnant women and in vitro fertilization.
3 And the reason that came out containing the concept
4 of beneficial research is that the Commission's
5 report on the fetus was issued before it had the
6 opportunity to engage in clarification of its
7 concepts which resulted in the Belmont Report.
8 Thank you.
9 DR. FLEISCHMAN: Mark.
10 MR. BARNES: I pass because I was standing
11 in queue for the procedural points.
12 DR. FLEISCHMAN: Jonathan.
13 DR. MORENO: It's not clear to me, Alan,
14 in the final analysis where we're going to stop, at
15 Subpart D when we're talking about pediatric research
16 or we're going to look at other regulations beyond
17 those that govern DHHS. Because, for example, the
18 Department of Education also has rules governing
19 research involving minors. So I guess I want to get
20 on the table that whatever we do with that -- well,
21 wait, my understanding is that NHRPAC and OHRP have
22 responsibilities beyond the concern about how
456
1 compliance with the common rule with the DHHS.
2 DR. FLEISCHMAN: Greg.
3 DR. KOSKI: I would just say, Jonathan,
4 that in this specific case there has been a specific
5 request made to NHRPAC on behalf of the Secretary and
6 the Department of Health and Human Services through
7 our office which has been charged with responsibility
8 for responding to Congress on a series of specific
9 questions that have been asked relative to Subpart D.
10 Given the time frame in which we have to
11 accomplish this goal, I would urge that while we not
12 preclude broader discussion in the future, that we do
13 all that we can to focus on the specific task at hand
14 which is to address those specific questions issued
15 by the Congress. Thank you.
16 DR. MORENO: I'm fine with that, but I
17 wanted to make it clear why we're doing D and we
18 definitely need to worry about education and others
19 to make sure that there is coherence with whatever we
20 come up with.
21 DR. KOSKI: The Department of Education
22 does subscribe fully to the common rule. And, you
457
1 know, certainly the provisions that -- as does
2 National Science Foundation and others, so that we
3 want to be sure as we think about research involving
4 children in the broadest context that we, you know,
5 understand the specific venues in which research is
6 conducted outside of the clinical trial.
7 DR. MORENO: Right. They subscribe to the
8 common rule, but not to D. They have their own
9 version of what we call D for DHHS. That needs to be
10 clear to everybody in the room who is concerned about
11 adolescence and kids in research. So that's why I'm
12 so concerned that we not -- after we do what Congress
13 wants us to do, we not stop there, but we go on to
14 look at other areas of pediatric research as we can.
15 My second comment has to do with -- is
16 somewhat related actually to what Abbey brought,
17 namely, we need to have somebody -- especially when
18 we're talking about adolescence, I think, and in
19 light of some of the controversies about pediatric
20 research, we need to have somebody who knows about
21 diversity research with kids who is at least a
22 liaison to the group. And Alan and I both, I think,
458
1 know people -- in New York -- for example who --
2 DR. FLEISCHMAN: Well, we've asked Dr.
3 Robert Murray from Howard to join us. He's agreed.
4 I certainly have some interest in that area. He has
5 more than interest. He's been a world leader in
6 discussion of both adolescent and sickle cell
7 research in children. So I think you're right. We
8 would be happy. I can speak as the -- is it chair in
9 the workgroup? Yeah. I guess it's chair of the
10 workgroup. The workgroup, I think, would be happy to
11 have other members with specific expertise and
12 advocates. We also, I think, would be happy to go
13 through a systematic review of the different standing
14 regulations or other authorities.
15 I tried to explain what the charge was to
16 this one six-hour meeting --
17 DR. MORENO: You did a beautiful job.
18 DR. FLEISCHMAN: -- in which we tried to
19 address a specific request of Dr. Koski and the
20 Secretary. And I don't think we've done a terrific
21 job. I think we've done an adequate job for the time
22 that we've --
459
1 DR. MORENO: Well, for six hours.
2 DR. FLEISCHMAN: -- we didn't do it.
3 DR. MORENO: I saw Dr. Murray's name
4 there. I guess what I had in mind was more survey-
5 oriented research which is the area that has tended
6 to be problematic with the diverse population. And
7 there are a couple of people who we can talk to about
8 getting involved and helping us with that.
9 I'm going to reserve my comment about
10 process until we do the housekeeping.
11 One comment I did have on research
12 involving adolescents in particular, since that's
13 what we're supposed to be talking about, is -- this
14 is what happens to you when you hang around a medical
15 school long enough -- I feel like I lack data about
16 how much -- what's the universe of experience that we
17 have with respect to research involving adolescents?
18 What do we know about what's actually been done? How
19 assent or consent has been accomplished.
20 I mean, I really feel a profound lack of a
21 database when we talk about this topic. And I wonder
22 how -- I'm assuming it's going to be very hard for us
460
1 to get that kind of information. But I think that
2 this is not the last time that we're going to have
3 this problem of lack of information about what the
4 experience has been with the regulatories.
5 DR. FLEISCHMAN: Actually, this is an area
6 where we know a great deal. There are many other
7 areas where we don't know a lot. The side of
8 adolescent medicine has been concerned about this
9 issue since its inception in the '80s. And in 1995,
10 they did publish some guidelines which are in your
11 packet. The society could give us the information
12 which assisted them in this regard. There are some
13 models of best practice out there. There are
14 guidelines. There are data about adolescent in
15 research. There had been a lot of discussion in that
16 area.
17 So we could amass that information for you
18 and I think it is available in this particular area.
19 Susan is agreeing with me. Because the field of
20 adolescent medicine, although it is fairly new, it is
21 as old as the regs, having been created in the '70s.
22 DR. MORENO: Right. I guess what would be
461
1 very helpful for those of us who don't know that
2 stuff is to have a presentation at another meeting,
3 maybe 15 minutes or so, laying out what the
4 experience has been.
5 MS. KORNETSKY: Yeah, I would just like to
6 add that I think in talking about that, we might want
7 to consider involving someone from the society of
8 adolescent medicine. I think they also have share
9 frustration that certain types of research
10 specifically in drug and alcohol abuse have not been
11 able to go forward. So I think that that would be
12 very, very helpful.
13 DR. FLEISCHMAN: Kate and then Felice.
14 MS. GOTTFRIED: I just wanted to say with
15 respect to adolescent medicine that I had contacted
16 on several occasions Renee Jenkins also from Howard
17 who is an expert in adolescence and unfortunately she
18 just had not ever returned any of my calls. So we
19 are still pursuing that with permission ultimately of
20 the committee.
21 DR. FLEISCHMAN: Felice.
22 DR. F. LEVINE: I took seriously the
462
1 charge of the working group and the construction of
2 it to be children or children and youth. I saw the
3 specific request that we focused on as directed to
4 Subpart D as currently implemented because there
5 needed to be a response, but that working group would
6 go well beyond that and that indeed I don't -- I
7 think that that would need to embrace all aspects of
8 social and behavioral research on children and youth
9 and that those would not be just restricted to the
10 social and behavioral science working group.
11 In that regard, I thank, in addition, the
12 Society for Research of Child Development, ARA, and
13 we've talked about having more of the texture of the
14 social and behavioral science perspective in each
15 individual working group so that there's much more
16 attention to that work done in other agencies beyond
17 HHS.
18 We tend to keep using the language of
19 health or adolescent health or surveys and we should
20 link to the work in adolescent medicine and when
21 indeed it's because of the centrality of health-
22 related concerns, appropriately so, for human subject
463
1 participation as well as in this group. But as we
2 are embracing all aspects of the combinant rule, this
3 workgroup will clearly have to be a lot broader.
4 DR. FLEISCHMAN: Mark.
5 MR. BARNES: I just wonder the extent to
6 which the issues of adolescent assent either in the
7 working group's deliberations or elsewhere has been
8 considered in light of local community conditions and
9 mores. Because I can imagine that -- well, we know
10 that in different States in Rhode Island versus --
11 heavily catholic Rhode Island versus heavily
12 protestant Alabama versus heavily agnostic California
13 that there are different rules --
14 [Laughter.]
15 MR. BARNES: That there are different --
16 will all due respect to Elliot.
17 [Laughter.]
18 MR. BARNES: That there are different
19 rules about what areas of health care in which
20 adolescents can consent for themselves according to
21 the different State rules and I wonder the extent to
22 which any kind of approach to these issues in
464
1 defining a particular assent process or kind of
2 laying out guidelines or considerations for IRBs to
3 make would take account of these local conditions or
4 local state -- which are really State statutes
5 because they're not local statutes.
6 And then just as a kind of an aside to
7 that, you know, in the HIPPA regulations that came
8 out, in regard to privacy of adolescents' -- of
9 medical records, including adolescents, the Clinton
10 administration actually punted on the issue and
11 basically said that nothing in HIPPA would violate
12 any particular state law regarding adolescents' right
13 to either consent to health care or to consent to
14 release of their medical records.
15 So, in fact, even the HIPPA regulations
16 which are really quite comprehensive in their draft
17 form really allowed -- they really stood aside and
18 let the States make all the decisions about
19 adolescent consent to disclosure of personal
20 information. So it's a long question, but that's the
21 question.
22 DR. FLEISCHMAN: Well, I think local
465
1 standards will be very important for IRBs to think
2 about and I know that in this area, like in many
3 others in research ethics, the HIV and AIDS world has
4 dramatically impacted on the adolescent world in
5 terms of the importance of developing approaches to
6 measure capacity in young people and allow them to be
7 in clinical trials when that was the really only way
8 that they could get the kind of cutting-edge
9 treatment that they appropriately deserved. So there
10 were areas like San Francisco and New York and Miami
11 where IRBs were -- and Newark -- where IRBs actually
12 were in the forefront of thinking about these issues.
13 And much of the work that came out of the
14 Society for Adolescent Medicine Guidelines in 1995
15 was actually generated by a good deal of interest
16 because of these young people and their needs. So I
17 think the local, both the laws and the culture and
18 the communities and the IRBs will reflect some of
19 this. What the workgroup has said though is that 408
20 allows for IRBs to make these judgments. To waive
21 permission of parents, but to set up a protective
22 process so that the young people can be protected,
466
1 determined to have capacity by whatever methodologies
2 that are appropriate and then counseled by people
3 independent of the research. And that IRBs can set
4 up these methodologies and allow adolescents then in
5 certain specific instances or certain specific
6 protocols to go forward without parental permission.
7 So those would all take into account the local mores
8 and standards.
9 Bob, and then I am going to open up after
10 Abbey to comments from our liaison and public members
11 on the issue of adolescents particularly and I would
12 like us to focus on adolescents so that we can get,
13 hopefully, this morning to the three other issues
14 that we also need to at least have some comments on.
15 DR. R. LEVINE: I was part of the Society
16 of Adolescent Medicine's group that worked on those
17 guidelines. And I wrote a paper that was published
18 in the same issue of the Journal of Adolescent
19 Medicine which went beyond the guidelines developed
20 by the group to attempt to see what would be
21 permissible under existing regulations. I did
22 acknowledge at the end of the paper that some of the
467
1 things that I read as permissible were highly
2 unfamiliar and that they shouldn't go ahead and do
3 them until they had the endorsement of some credible
4 national deliberative body.
5 I want to say that one big problem area
6 that's been presented particularly to those who want
7 to study adolescents' risk behavior is the standoff
8 between the requirements of the regulations and
9 practicality. If you want to -- I've been involved
10 with one group of anthropologists whose problem is
11 that they want to track very young adolescents, what
12 I call middle-aged adolescents, 13, 14. They have a
13 way of identifying risks of which ones are more
14 likely than average to enter the hard drug abusing
15 culture. They want to do some, you know, work
16 attracting them as they go into this culture.
17 Frankly, my fear is more for the anthropologists than
18 anyone else.
19 [Laughter.]
20 DR. R. LEVINE: But they had this problem
21 that when you're dealing with a 13- or a 14-year-
22 old, it's very hard even in those States who say that
468
1 young people or old adolescents can get counseling
2 for drug abuse without their parents' awareness or
3 permission. When you're getting down at those age
4 levels, it's very hard, especially since these people
5 are not seeking counseling and don't yet have the
6 problem. But if they say, we have to get your
7 parent's permissions, there is not going to be any
8 research. So I think that's something that I would
9 like to see addressed by the group. Thank you.
10 DR. FLEISCHMAN: Abbey?
11 MS. MEYERS: In terms of the controversy
12 that led to this whole examination of what's
13 happening with children, it's because of a 1997 law,
14 the FDA modernization act which has a little
15 amendment in it that calls for pediatric exclusivity
16 which is, if you study a drug for use in children
17 which leads to the relabeling of the drug for
18 pediatric uses, you get six more months of exclusive
19 marketing rights. And since most drugs are labeled
20 for children over eight or children over 12, it led
21 to a huge upsurge in pediatric research on drugs that
22 are primarily used for adults. And it's not the
469
1 drugs that children really need, it's more or less
2 the drugs that are the biggest selling drugs. So the
3 focus is on getting arthritis drugs approved for
4 children. And some children are going to need
5 arthritis drugs.
6 So that raises questions of whether some
7 of these drugs are being used improperly on children
8 just for the sake of getting them through the testing
9 process, et cetera. And whether there's truly an
10 informed consent in many of these cases. I mean, I'm
11 waiting for the studies to -- pediatric studies on
12 Viagra and then maybe people will say something is
13 wrong here.
14 So the question here is not really
15 adolescence in effect. What is the political
16 question now. The question is, children about ten
17 years old and younger is where the focus is.
18 DR. FLEISCHMAN: Actually, the workgroup
19 at its first conversations was concerned precisely
20 about the opposite issue that you raised. And that
21 is, the pediatric community, the clinical pediatric
22 community is terribly concerned that the vast
470
1 majority of medications being used in children today
2 have never been tested in children. And that the
3 pediatric community applauded the approach both that
4 the NIH and the FDA have taken to try to increase
5 clinical trials in children.
6 At the same time, both of those agencies
7 made it clear to the pediatric community that there
8 would be no decrease in the standards of regulatory
9 approach nor decrease in the research ethics
10 requirements which would be monitored and supported
11 through IRBs and through the regulatory structure.
12 The pediatric community, at least as both
13 reflected in this workgroup and in many other
14 conversations I've had, was quite pleased that there
15 are now most pharmaceutical companies willing to
16 embark on what are more difficult trials, more
17 expensive trials, for all of the reasons that we
18 understand and that is the consent processes are more
19 complicated, the monitoring needs to be more careful.
20 It requires more staff to do these studies. But the
21 pediatric community was comfortable both with the
22 increasing numbers of research studies because of the
471
1 need and with the maintaining of tight scrutiny of
2 the standards of research ethics. The committee
3 actually began with one of its outside members quite
4 upset. A national leader in pediatric infectious
5 diseases quite upset at most of the antibiotics that
6 he uses, most of the medications that he uses have
7 never had adequate study in the pediatric community;
8 harming, in his opinion, far more children than have
9 ever been harmed in randomized clinical trials that
10 are carefully done.
11 So I think it is important that we realize
12 there was some change in the FDA. There was some
13 change in the NIH in terms of its desire to
14 rationalize research in terms of women and children.
15 But that there were no changes in the standards that
16 we're obligated to maintain. And I don't think there
17 are data to support that the standards have been
18 generally overridden or not maintained.
19 There is also no requirement that a drug
20 that has no usage in children be tested in children.
21 And, you know, I think the comment about drugs that
22 don't have appropriate uses in children just -- you
472
1 know, I don't think that that's a fair assessment of
2 what either the pharmaceutical industry nor the
3 pediatric community would allow in terms of children.
4
5 MS. MEYERS: The drugs that need most to
6 be tested in children, Ritalin has never been because
7 the patent is gone.
8 Antibiotics where they're patents are
9 gone, nobody is doing the pediatric studies because
10 there's no exclusivity for an unpatented drug. And
11 so the focus has really been on the drugs that are
12 most lucrative. The asthma drugs are still not being
13 tested on children.
14 DR. FLEISCHMAN: We did hear at the last
15 meeting the commitment of the National Institutes of
16 Child Health, and Dr. Alexander is here, to try to
17 help to get some of that research accomplished. And
18 I would have to say that many of the drugs that you
19 have mentioned have had studies done and that there
20 are randomized clinical trials of various
21 methodologies. Is it perfect, has it been completed,
22 is the last word in? No. But that's the reason why
473
1 we need to look at these regulations so that those
2 who wish to do such work could do it in a safe and
3 effective way.
4 Mark?
5 MR. BARNES: Can I ask a quick question.
6 I had thought that -- and maybe I don't really
7 understand the law and the regs here, but I had
8 thought that before any of these trials could
9 proceed, or these adult approved drugs could proceed
10 with children, that there was a very careful FDA
11 screening process; am I wrong about that?
12 DR. FLEISCHMAN: Well, perhaps we could
13 as, our representative on the workgroup from the FDA.
14 If you would introduce yourself and tell us your
15 thoughts about that.
16 DR. ROBERTS: I'm Rosemary Roberts and I
17 work for the Center for Drugs on the Pediatrics team.
18 You are correct, Mark. The statute indicates that
19 the FDA is to request the studies to be done at the
20 sponsors. So although we have asked sponsors to send
21 in proposals of pediatric studies so we know who is
22 interested in doing trials, once those proposals come
474
1 in, they are looked at by the appropriate regulatory
2 division and we determine if there is indeed a public
3 health benefit that would be gained by studying these
4 products in children so that we can get them
5 appropriately labeled.
6 And once that is done, then it's
7 determined what kind of studies are necessary in
8 order to be able to get that information. So the FDA
9 is very much in the driver's seat as to what studies
10 are being requested of industry.
11 Now, we certainly have heard the criticism
12 that indeed it's the lucrative products that have
13 been getting to the gates first. And, indeed, many
14 of the products that have been granted exclusivity
15 have been some of the blockbuster drugs. There are
16 also some drugs that are not blockbusters that are
17 being studied too. And we are concerned about the
18 antibiotics and we are concerned about the drugs that
19 are off patent because they have fallen in the crack.
20 There is nothing for them to gain.
21 And as we are working now and as there are
22 many people interested in the renewal, one of the
475
1 areas of greatest interest is, what can be done about
2 those products that have not benefitted from this?
3 But we are requesting the studies and we
4 look very carefully at the information we have and
5 what's necessary and we put that request out. And
6 industry then has to meet the terms of that request
7 in order to qualify.
8 DR. FLEISCHMAN: Thank you. And Dr.
9 Roberts is on our workgroup and has been helpful
10 thee. I would comment that in the workgroup report
11 we did not accurately depict what Dr. Roberts just
12 described and on page 2 she's given us some new
13 language to put into the report and that will be
14 done.
15 Adil and then Rabbi Dorff.
16 DR. SHAMOO: I just want to state that
17 what she said is true, if it's FDA busters in IND
18 applications. All the NIH-funded research in
19 children does not follow the same process. As a
20 matter of fact, NIMH just funded research in two to
21 four years old, two to six or two to four on Ritalin,
22 Abbey, as a matter of fact. A large number of -- as
476
1 a preventive measure, as a matter of fact, which is a
2 very disturbing type of -- protocol.
3 So, FDA is not in the drivers' seat for
4 all the proposed research in children and we should
5 keep that in mind. And also we should keep in mind
6 that the pharmaceutical industry, if it is not IND
7 type of research, they will do that research. They
8 do that research by privately funding some hospitals,
9 some academic centers to conduct research and there
10 is one of them at Yale University.
11 Dr. Levine I am sure can correct me if I'm
12 wrong, he will jump immediately -- and that is --
13 [Laughter.]
14 DR. SHAMOO: -- and that is that it's a
15 privately funded, at least the Wall Street Journal
16 Report indicates 1,400 children to prevent
17 schizophrenia from occurring. Even though the
18 chances of schizophrenia occurring in those children
19 is no more than 10 percent.
20 DR. FLEISCHMAN: Elliot.
21 DR. DORFF: I just wanted to respond
22 directly to the question that you asked at the end of
477
1 your presentation just so that you know that it was
2 at least heard.
3 I do think that the degree of risk is an
4 important thing in terms of figuring out what drugs
5 should be or what -- not just drugs, but other kinds
6 of protocols of research should be used with children
7 -- with adolescents, in particular, and I think one
8 of the real issues that you get in this in regard to
9 adolescents is the same that you had with adults, but
10 more so. Namely that you have to figure out who is
11 judging. Whether the adolescent understands the
12 degree of risk.
13 And I think that, you know, the greater
14 the risk, definitely the greater precautions that you
15 have to -- that we have to take and we have to build
16 into the regulations. And among those precautions
17 are people from outside the whole protocol who are
18 willing and able to make sure that the adolescent
19 understands what's going on.
20 DR. FLEISCHMAN: Yes. And in the guidance
21 of the Society for Adolescent Medicine, that's
22 precisely the approach that they recommend. Within
478
1 what they believe to be the regulations as they stand
2 now IRBs have the capacity and the authority to make
3 such determinations to moderate risk versus the need
4 to determine capacity, the need to have counselors
5 available outside of the research, and the need to
6 monitor the whole consent process and ongoing
7 research. And that's what has been recommended and
8 IRBs actually in several parts of the country are
9 actually doing that based in 408 in the regulations.
10 I think it's Felice and then Bob.
11 DR. F. LEVINE: Maybe a complimentary
12 point because I was going to bounce off of Bob's
13 point. While we talked about addressing this with
14 respect to DHHS, I would like to commend in the
15 spirit of the language of this document that when we
16 talk about assent and consent and the capacity to age
17 and staged appropriate for the child to invoke assent
18 without necessarily consent that we recognize and use
19 examples that are not just grounded in clinical
20 trials, that much of the work supported by NIH
21 includes non-clinical, social/behavioral research and
22 that we want to be and are included under this and we
479
1 have often used that provision to permit very
2 important work on runaway kids on youth networking,
3 at-risk youth and the evolution of gang formation and
4 other kinds of work where parental consent or
5 parental written consent is not known or even
6 possible.
7 So I think working in some examples
8 irrespective of the common rule in what goes on in
9 other agencies just within the family of terrific
10 work supported by NIMH, NICHD, NIADA and others we
11 should include in this.
12 DR. FLEISCHMAN: Bob?.
13 DR. R. LEVINE: I'm sorry Abbey isn't in
14 the room right now, but I wanted to point out that
15 Abbey is very concerned that Ritalin is not being
16 studied and Adil is very concerned that it is.
17 The fact that something is not reviewed --
18 not being done under an IND does not mean that there
19 will not be rigorous review.
20 In fact, I believe that the review that
21 one gets at NIH when you're applying for a grant or a
22 contract is at least on a par with that provided by
480
1 FDA where you have a goodly number of experts and
2 people who are concerned about the well-being of
3 children evaluate applications for grants and
4 contracts.
5 The statement that there are private
6 interests that are funding research that is not
7 regulated by anybody is counterintuitive. Why on
8 earth would anybody want to study a drug without
9 getting an IND when if they don't get an IND they are
10 not eligible to apply for a change in the package
11 label.
12 Any time that there is a commercial
13 interest there has to be an IND or else it's an
14 exercise in futility.
15 Thank you.
16 DR. FLEISCHMAN: I'm going to ask for our
17 liaison and public members if they have comments
18 about the issue of adolescent consent to please come
19 to the microphone.
20 And if you would identify yourself.
21 DR. RUBIN: These are a little general,
22 but they do -- I'm going to just try to restrict it
481
1 to the portion on adolescent assent; consent is a
2 little difficult.
3 Phil Rubin from the National Science
4 Foundation, ex officio. Sorry I stepped out of the
5 room for a moment before, but it was pointed out that
6 the National Science Foundation hasn't adopted
7 Subpart D and because we think in certain cases it's
8 too restrictive. For example, in this case,
9 regarding the appropriateness of regulations of
10 children of differing age, we feel the regulations
11 are overly restrictive for normal behavior and social
12 science research and are not appropriate for the kind
13 of no-risk and minimal risk research that we normally
14 support.
15 Related to that is, basic research does
16 not promise direct benefits to participants and the
17 regular provisions and the common rule supply
18 adequate protection. We've been over and over this
19 and I just want to make kind of a little note on that
20 and we've provided detailed comments. And so we have
21 specifically written that regarding Subpart D, if
22 there's going to be a recommendation from this group
482
1 that there's a federal-wide adoption of Subpart D
2 that once again we understand the constraints that
3 the group is under and the need to respond, and we
4 would like to actively work with you.
5 But if there is going to be a
6 recommendation of this group, please alert us so that
7 we can get our General Counsel involved because, once
8 again, we're trying to work and that's not something
9 that we feel needs to be done. But it's just kind of
10 particular. If something like that is going to be a
11 recommendation, we would like to be even more
12 actively involved as part of the process. At the
13 moment we are happy with what is going on.
14 DR. FLEISCHMAN: Other public comments?
15 Liaison comments?
16 [No response.]
17 DR. FLEISCHMAN: We are going to take a
18 ten-minute break. We will come back to continue
19 working through the workgroup's recommendations. Ten
20 minutes.
21 [Brief recess taken at 10:23 a.m.]
22 DR. FLEISCHMAN: We are going the move on
483
1 with the next major issue. And it speaks to the
2 second question asked of the Secretary by Congress
3 and that has to do with the issues around minimal
4 risk, definitions, and applicability.
5 Reminding you that "minimal risk" was
6 defined in 46.102 as meaning, "the probability and
7 magnitude of harm or discomfort anticipated in the
8 research are not greater in and of themselves than
9 those ordinarily encountered in daily life or during
10 the performance of routine physical or psychological
11 examinations or tests."
12 The workgroup concluded that that
13 definition was essentially acceptable and should be
14 considered an absolute standard. Realizing that
15 these were the socially acceptable risks to which the
16 society places children in the normal daily average
17 routine, visiting the doctor, going to the dentist,
18 receiving routine care, playing at home or with
19 friends as well as the routine kinds of psychological
20 testing that children generally have.
21 Now, here the committee felt -- or, excuse
22 me, the workgroup felt that minimal risk considered
484
1 as an absolute standard --
2 [Laughter.]
3 DR. FLEISCHMAN: -- I'm sorry --
4 [Discussion off the record.]
5 DR. FLEISCHMAN: No, actually, just to
6 comment. I didn't say this yesterday to Mark, and
7 I'll wait until he gets back, but his workgroup
8 report used NHRPAC in its language. Our workgroup
9 report uses "workgroup" in its language. And I think
10 that's an important distinction, so I'm holding to
11 that.
12 The issue then was socially acceptable
13 risks for average and normal healthy children. These
14 are issues that have been debated and have been
15 controversial over the years. The feeling of the
16 workgroup was that this needed clarification and we
17 have all had distributed to us a draft report from
18 what has been called the "407 Committee".
19 Now, you'll be reminded that Section 407
20 of the regulations speaks to those research proposals
21 who are not otherwise permitted through the
22 regulations, but could be permitted through a process
485
1 which would include the Secretary's approval after
2 public comment and review at the federal level.
3 In fact, there has been a small group that
4 has been convened in order to review some proposals
5 through that approach, and they gave us the benefit
6 of their wisdom in looking at the process of 407
7 review as well as setting certain approaches or
8 standards. The workgroup read that report. It
9 didn't endorse it in its entirety, but believes it's
10 a very important helpful document to help us in our
11 analysis.
12 And in that report the committee suggested
13 daily life is interpreted to mean the daily life of
14 healthy children in the general population. It
15 wasn't the general life or daily life of a child in a
16 socially deprived environment or a child perhaps
17 internationally in an environment where there might
18 be guns firing over their heads, it was felt to be
19 the daily life interpreted of healthy children in the
20 general average population.
21 This becomes important when we consider in
22 the next grouping the concept of minor increment over
486
1 minimal risk and the definitions of disorder or
2 condition.
3 To remind you, in 46.406 which basically
4 speaks to research involving greater than minimal
5 risk and no prospect of direct benefit to individual
6 subjects, but likely to yield generalizable knowledge
7 about the subject's disorder or condition. This is a
8 group of research projects that are permissible
9 through IRB review, but there are certain specific
10 codicils that go with that review.
11 First, the magnitude of the research risk
12 must be small, above minimal. A small increment.
13 That's why the word "minor."
14 And, second, that experience has an
15 experiential qualifier. The experience of the
16 intervention is reasonably commensurate with those
17 inherent in the research participant's actual or
18 expected medical, dental, psychological, social, or
19 educational situations.
20 Now, those, I think, are important parts
21 of that subsection which the workgroup believed were
22 appropriate needed clarification with examples, but
487
1 were an appropriate method for IRBS to determine
2 which types of research might be allowed or
3 permissible in children who had a disorder, disease,
4 or condition.
5 Now, the concept of condition has had some
6 conversation as well. The workgroup attempted a
7 first look at this problem. And it felt -- on the
8 top of page 6 -- a relevant condition addresses those
9 aspects of the environment that impact on the child
10 such as the biologic, environmental, social,
11 emotional and behavioral determinants of the child's
12 well-being.
13 Thus, on the one hand poverty might be
14 considered a relevant condition, social condition
15 worthy of careful scrutiny. And on the other hand, a
16 genetic or familial predisposition to a disease or
17 disorder might be a relevant biologic or social
18 condition which places a specific child outside the
19 purview of normal, average, healthy children.
20 This is the way the workgroup is
21 recommending that we deal with the concept of minor
22 increment over minimal risk and the concept of
488
1 disorder and condition.
2 I will pause here to take comments from
3 the group. I'll start with Jonathan and then Abbey.
4 DR. MORENO: Let's start with the notion
5 of minimal risk as absolute. And this actually
6 applies, of course, not only to D, but to the common
7 rule generally. I have heard Greg's predecessor say
8 publicly that this is the understanding of the
9 predecessor agency of the meaning of minimal risk.
10 And I think it's important to get on the record that
11 your interpretation is not the first interpretation
12 that goes to this point that it's an absolute
13 standard.
14 Though -- and maybe somebody from OHRP can
15 help me with this -- when I go to the OHRP web site,
16 I look for a guidance or a "Dear Investigator" letter
17 to put this on the record. Now, maybe there is
18 something on the record in some guidance in the
19 earlier -- a decade ago or when I was too young to
20 read, but --
21 DR. FLEISCHMAN: That was more than a
22 decade ago.
489
1 [Laughter.]
2 DR. MORENO: It would be worth whatever
3 the document that's finally produced, it would be
4 worth, it seems to me, referencing any official
5 statement to this effect. Because I have
6 encountered, even now, IRB educators who interpret
7 this as a relative standard.
8 DR. FLEISCHMAN: May I use this
9 opportunity to remind the committee and our other
10 members that it is the recommendation of this
11 workgroup that a series of memoranda, we can call
12 them whatever the appropriate language will become,
13 clarifying several areas, including this one. The
14 workgroup is recommending that we develop such
15 memoranda or guidance -- or whatever the appropriate
16 language of art will be -- as we move forward, which
17 will interpret the regulations. That is the
18 workgroup's hope. And those, of course, would have
19 hopefully a background or historical context, some
20 information about what the bases would be for such
21 and then the specifics as well as some specific
22 examples which we think will be helpful to IRBs that
490
1 aren't chiseled in stone, but would then be able to
2 be evolving as new problems come up over time.
3 You know, there were no MRIs ten years
4 ago. There were words to read, but there weren't
5 MRIs ten years ago. There were no -- so, you know,
6 we would need to have a fluid document that would be
7 able to get some examples. I have Abbey and then I
8 have Susan and then Sandy.
9 MS. MEYERS: Well, I want to know how this
10 section that you just went over would affect healthy
11 children in a placebo group? Children who don't have
12 the illness, and, for example, I think I've been
13 hearing about a study for an antibiotic because on
14 otitis media and they're going to be studying
15 children who don't have otitis media, perfectly
16 healthy kids, because the likelihood is they will
17 have otitis media sometime during their childhood.
18 And the second thing is, and maybe Greg
19 can answer this, there was a study by NIH which I
20 believe your office closed down on studying healthy
21 children of obese parents who were put through a
22 series of extraordinary tests. You know, tests high
491
1 blood sugar, low blood sugar, and so forth, just to
2 monitor them to see if they would come down with
3 diabetes eventually. Again, these were healthy
4 children.
5 DR. FLEISCHMAN: I'm going to ask us to
6 hold off on the placebo discussion until we actually
7 have a full discussion of placebo-controlled trials
8 which is coming soon to this table in the next few
9 minutes. So let's hold off on that one, but I will
10 ask if Greg wants to comment on the issue relevant to
11 children in a family having been subjected to -- been
12 subjects of research to look at a predisposition
13 toward future illness?
14 DR. KOSKI: I'm not going to go into
15 details about the specific study in question except
16 for the fact that there are some elements of that
17 that have already been discussed. It was a study in
18 children of obese parents who had a strong
19 predisposition of developing obesity, studies
20 directed toward understanding the metabolism in
21 children and so it's a study that is, you know,
22 currently still in process and I won't comment about
492
1 that further. But, again, I think it's very
2 important of we again have this discussion, the
3 dialogue about, you know, how we consider risks and
4 have the disorder really is.
5 DR. FLEISCHMAN: I think that the
6 workgroup -- I'll give you a moment if I can just
7 comment on this. Thank you.
8 The workgroup did not review that specific
9 protocol. But did speak about the concept of
10 condition. And I don't know that protocol. So I'm
11 not going to comment on it specifically. But the
12 workgroup did argue that a predisposition, whether
13 genetic or social, toward future illness would allow
14 IRBs to place such research into this category that
15 obviously have to review it.
16 They would obviously have to consider it,
17 they would obviously have to consider what a minor
18 increment over minimal risk was, but that this
19 workgroup, just so we're clear on this, would argue
20 that there are certain conditions that would allow
21 children who were asymptomatic from specific disease
22 or diagnosis at this time to have minor increment
493
1 over minimal risk research because of either genetic
2 or social factors, biologic, or others that would
3 predispose them. And this was what the workgroup is
4 trying to talk about at the top of page 6. And now I
5 have Susan, Sand, Bob, and Adil on the docket here.
6 MS. KORNETSKY: Just quickly going back to
7 Jonathan's comment about the absolute or relative and
8 was part of the working group and I support --
9 DR. FLEISCHMAN: Excuse me, please.
10 MS. KORNETSKY: -- I support the position.
11 I do want to point out and I think it was pointed out
12 yesterday that one of the books that IRBs often use
13 and they are to train and for themselves something
14 that the OHRP put out a while ago, the IRB guidebook,
15 and there is some conflicting information about --
16 specifically about how to interpret the standard.
17 And I know yesterday there was discussion about
18 genetics. And although I realize there are guidance
19 letters and there's no guidance specifically on this,
20 but if there are portions of that guide book that do
21 not pertain anymore are being evaluated, it would be
22 helpful for the community to know that.
494
1 DR. FLEISCHMAN: Sandy.
2 DR. CHODOSH: I want to get back to this
3 business of the minimal risk, because, you know,
4 despite the fact that I've been involved with this, I
5 can't tell you how many decades, there is still a lot
6 of confusion about how an IRB looks at minimal risk
7 and how a subject looks at minimal risk. And I think
8 that it's an argument that I had with Charlie
9 McCarthy many years ago that to me minimal risk,
10 something above minimal risk depends on what the
11 person has. And that if you don't take that into
12 consideration, you are not being realistic about what
13 patients expect or what subjects expect.
14 Subjects who are already suffering from
15 shortness of breath say, with my kind of diseases,
16 chronic bronchitis and emphysema, don't consider have
17 a pulmonary function test at any risk whatsoever.
18 Don't consider having a chest X-ray any risk
19 whatsoever. This is within their normal framework of
20 how they look at things and one should -- I know that
21 there are IRBs which will view that and take that in
22 consideration as opposed to this business of just
495
1 above minimal risk for a healthy person.
2 This concept of the healthy person doesn't
3 really relate to patients. And if we're protecting
4 subjects, we should look at it from both sides. We
5 are not really protecting them if we sometimes keep
6 them from having adequate research because we think
7 that maybe the risks are too great, even though
8 they're the same risks that they have from having
9 their disease.
10 DR. FLEISCHMAN: Sandy, just to respond, I
11 think one of the great pieces of wisdom that the
12 National Commission did here was to precisely
13 separate out those children who had a disease,
14 disorder, or condition which would then allow for
15 such similar kinds of work as the work you're
16 describing in those adults with chronic obstructive
17 pulmonary disease. And that allowed then for this
18 concept of minimal or even minor increment over
19 minimal to be a permissible level of risk for those
20 children who had that experience as you described for
21 adults.
22 DR. CHODOSH: I think what I'm saying is I
496
1 have seen such confusion among IRBs as to how you
2 look at this, that it needs to be clarified more than
3 on paper. I think we need to have an educational
4 process that really is devoted toward the point of
5 you, what does the subject expect, and I think that
6 IRBs act differently in this regard and it goes back
7 to a lot of problems that we have with IRBs and how
8 they view things, but we'll get to that later at some
9 other point.
10 DR. FLEISCHMAN: Thank you. Bob.
11 DR. R. LEVINE: Thanks. I agree with both
12 Sandy and Alan. The Commission -- National
13 Commission necessarily left the definition of "minor
14 increase" vague. I think the idea that Sandy is
15 trying to get across is what you find in the criteria
16 for justification of minor increases. This
17 particular one is that the procedure must be
18 commensurate with what would be expected in the
19 child's actual life experience given the condition or
20 disease the child has. So children in Sandy's
21 practice would find pulmonary function tests and
22 chest X-rays highly familiar.
497
1 I want to emphasize that the purpose of
2 putting in the commensurability standard was not to
3 say, well, here's a kid with leukemia who is going to
4 have ten bone marrows anyway, another one won't hurt,
5 was really meant to make it possible for the child
6 prospective subject to understand what was being
7 proposed to say, we're proposing to do a bone marrow
8 examination, but this is one you don't have to have.
9 And the kid can say, "Oh, I know what you're talking
10 about, I don't want that."
11 The other point I want to make is that in
12 the 20-some odd years since the Commission made its
13 recommendations on this topic we have had multiple
14 case reports, analytic case reports of actual
15 experiences of IRBs, many of these are published in
16 the IRB journal. And what they do is tell us the
17 reasoning that went into a decision by a particular
18 IRB to call something either a minor increase above
19 minimal risk or no increase, and I think we can
20 profit from those. Even though it's not specified in
21 any regulation, you get the general sense that a
22 minor increase would include such things as lumbar
498
1 punctures, bone marrow aspirations, things of this
2 sort, but they would not include left heart
3 catheterization and some other things like that.
4 Thanks.
5 DR. FLEISCHMAN: Adil.
6 DR. SHAMOO: I don't know if you looked at
7 the NBAC's recommendations on this issue of minimal
8 risk and they discuss it very much indeed here and
9 they weigh in, in that that should be an absolute
10 standard. They took the probability of harm and the
11 magnitude of severity and potential of harm that they
12 can very specific -- they made specific
13 recommendations that said, "should not be left to the
14 discretion of one local IRB, but rather should be
15 reviewed by a national review panel with public input
16 into the review process." And that would be the
17 method I would take.
18 That if you leave it to the local IRB, you
19 will see the confusion Sandy is talking about and
20 others have been talking about and you will see the
21 slippery slope, one IRB doing something and another
22 IRB doing another and then 10, 15, 20 years from now
499
1 we'll be back on square one.
2 Having said that, let me go back to what I
3 really wanted to ask and that is the condition. We
4 really need to discuss -- because condition I bet you
5 in this entire room we all have some genetic
6 predisposition to something. So we have all
7 conditions. The question is, is the risk to the
8 children for the future, are we talking about we're
9 going to consider the condition and therefore make
10 allowable research on them if the risk is .1 percent,
11 1 percent, 5 percent, 10 percent, 20 percent, 50 -- I
12 could understand it if you tell me it's 90 percent.
13 I could understand if you tell me even 60 percent. I
14 may even consider 50 percent. But now we have
15 research that's being proposed for this quote/unquote
16 condition that's in the 5 to 10 percent.
17 I wouldn't want my child to go into
18 research as a subject because he has a risk 5 to 10
19 percent to contracting disease A or B or C. And this
20 is the exact example I just brought up a few minutes
21 ago about schizophrenia research. Siblings of
22 schizophrenic children have a somewhere between 5 to
500
1 10 percent risk. That's considered a condition and
2 that was a justification used for using preventive,
3 modified risk experiment, a very powerful drug.
4 You're talking about Haldol, Clozapine, Respiradol
5 type of drugs.
6 And we really need to wrestle with that
7 issue and come one way or the other. What is the
8 percent risk we consider a condition. If you just
9 say the word "condition" forget it. It's meaningless
10 because we all have conditions.
11 DR. FLEISCHMAN: Abbey.
12 MS. MEYERS: I just wanted to say after
13 you had introduced this whole section that it seems
14 to cancel out the other section on placebos. Because
15 here we're talking about protecting healthy children
16 who don't have symptoms and yet in the other area
17 we're talking about giving healthy, asymptomatic
18 children some kind of tests, whether it's a blood
19 test, or X-ray, or whatever, there's some risk in it.
20 DR. FLEISCHMAN: Elliot.
21 DR. DORFF: I just wanted to at least make
22 it clear for myself if for nobody else, that if we
501
1 take Sandy's point seriously, then the language that
2 you have here on page 5, "The workgroup concluded
3 that minimal risks should be considered an absolute
4 standard" would be incorrect because then "minimal
5 risk" would be -- if I understand you correctly,
6 right, then "minimal risk" would be defined according
7 to the particular condition, I'm sorry, that the
8 child has; right? So that in other words minimal
9 risk for an asthmatic child would be different in
10 terms of tests about, you know, lung function and the
11 like, than for a child without asthma.
12 So, I mean, I don't know where we want to
13 go with this, but I think we should be at least
14 clear.
15 DR. FLEISCHMAN: Let me clarify the
16 workgroup's thought on this. That minimal risk would
17 not be different, but that children with asthma have
18 a disorder or condition or disease in that case which
19 would allow for research to include a minor increment
20 over minimal risk even if there was no intended
21 therapeutic or beneficial arm.
22 So that if we had children with asthma and
502
1 we were looking at various interventions, education
2 interventions, other kinds of things, we could, as an
3 IRB, look at a different level or risk than minimal.
4 Minimal being the average normal healthy child and
5 through this 406 section children with asthma having
6 a condition could then have those kinds of studies
7 that Sandy is talking about.
8 The workgroup would like to keep the
9 definition of minimal risk absolute and that is
10 compared to the average daily life of a healthy
11 normal child, but reminds us that there is another
12 category which is why Adil's point about what
13 constitutes a condition is an important one because
14 the workgroup is arguing that the IRB is going to
15 have to consider that. The workgroup has not done
16 the work that Adil has suggested. I don't know if it
17 would wish to, and that is try to put a percent on
18 different things. I mean, 5 percent risk of very
19 serious illness, to me as a clinician, sounds quite
20 significant actually. But, you know, I don't -- a 60
21 percent risk of a significant illness to me as a
22 clinician is overwhelming. I mean, it requires very
503
1 different review, having nothing to do with research,
2 having to do with clinical care.
3 So, for me, as an IRB member, if I were
4 sitting with an illness that had a 5 percent
5 incidence serious illness or disorder, I would be
6 very comfortable -- and I tell you this very
7 personally and having nothing to do with this
8 document, I would be very comfortable with reviewing
9 research that would look at predisposition for that
10 problem, try to help us as clinicians to understand
11 which children need more interventions, preventive
12 interventions, or whatever.
13 So I think the workgroup is trying to
14 argue that IRBs need to learn that there are such
15 conditions, some of them are biologic, some of them
16 are social, but that are important to child health
17 which would then allow for the IRB to consider the
18 minor increment over minimal risk category.
19 When we looked -- "we" meaning when I
20 looked at the NBAC report, particularly the NBAC
21 report on adults with mental disorders, who had
22 questionable capacity in order to determine whether
504
1 they could participate in research, I have to tell
2 you that I disagreed with their categorization of
3 minimal risk and everything else.
4 What I believe they were asking of us as a
5 community of researchers is to go down a slippery
6 slope and to add into the minimal risk category
7 things that would not be in the minimal risk category
8 in the present definition in my opinion. But they
9 asked us to do that because they eliminated the minor
10 increment over minimal risk category. And that, I
11 think, for the sake of children, is a better approach
12 for IRBs than to try to shoehorn into the minimal
13 risk category things that are not in the experiences
14 of average healthy children.
15 So that was my personal response to the
16 NBAC report when they wrote that one. Their most
17 recent report does lean heavily on that approach in
18 terms of their consistent view of this. Now, if
19 there are people who are from NBAC or have other
20 views of that, I'm happy to have them come to the
21 microphone and talk about it. But from the
22 perspective of the children's regs, it would be
505
1 different than the NBAC recommendations and from this
2 observer, it gives the IRBs a much better, more
3 carefully constructed and thought out way to protect
4 children.
5 Adil.
6 DR. SHAMOO: What you missed from there,
7 you didn't mention that the proposed intervention --
8 if the proposed intervention has no value, there are
9 no data indicating it's preventive to that disease in
10 the future, why do it. It's a fishing expedition.
11 And most of the research, some of that is being
12 proposed. They have no clue that the drugs used to
13 relieve symptoms necessarily will prevent the
14 occurrence of the disease, and that is the one we
15 should worry about. I personally don't think you
16 would approve, even if 5 percent where the
17 intervention is high risk like Clozapine or
18 Respiradol, and there are no data whatsoever that
19 would prevent the occurrence of the disease ten years
20 later.
21 And the scientist -- are horrible.
22 DR. FLEISCHMAN: Well, I'm not going to
506
1 get into the specifics of that research project, but
2 it is certainly in my opinion the responsibility of
3 the IRB to begin with a careful assessment of the
4 scientific rigor and validity of the hypothesis and
5 the questions being asked.
6 DR. SHAMOO: -- are being accrued by IRBs
7 and that's why I don't want to depend on local IRBs
8 all over the country each having their own standard
9 rather than a national or regional IRB where these
10 things are discussed at public hearings and deciding
11 those terms -- not each local IRB.
12 DR. FLEISCHMAN: The workgroup in its
13 conclusions will request that we carefully think
14 about IRB accountability and monitoring of IRBs
15 whether or not it results in having national IRBs.
16 The workgroup will recommend, as you will see at the
17 end, that we need to develop measures of
18 accountability for IRBs both prospective
19 credentialing as well as post hoc evaluation and
20 accountability of IRB practices which I think is
21 going to be a great challenge for the field of
22 research ethics.
507
1 But the workgroup is certainly cognizant
2 of the importance, Adil, of what you're arguing, and
3 that is that there needs to be some accountability of
4 local review at some kind of structure or regional or
5 national level.
6 I have Mark and then Jonathan and Greg.
7 Bob before Greg.
8 MR. BARNES: This is related to a point
9 that Adil made earlier. I think that there really is
10 some need for conceptual clarity about what these
11 regulations regard as a child having a condition or
12 subject to -- subject's disorder or condition and
13 there are some concepts in the law of employment
14 discrimination related to disability and particularly
15 genetic discrimination that are actually very
16 applicable here. And let me just briefly, you know,
17 kind of give you three different cuts on what it
18 might mean. Okay. Just briefly.
19 Maybe subject to a disorder means that the
20 individual child has a proven higher probability of
21 developing a particular condition over time. Or it
22 may mean that the individual child has an
508
1 individualized risk of developing a particular
2 condition at any point in time, or it may mean that
3 the individual child is a member of a group defined,
4 however you wish to define it, by race, ethnicity,
5 poverty status, income level, geographical residence,
6 environmental exposures, et cetera, where the group
7 has an epidemiologically sound probability or
8 epidemiologically proven probability of its members
9 developing a condition at a particular point in time
10 over whatever time period you want to define it.
11 And then in any of these or in more,
12 because you could spin out, you know, many more
13 permutations of what it means to have either
14 individualized risks or being an individual that's a
15 member of a group that has a heightened risk, then
16 you also have to reach the point of what is the
17 probability breakpoint on the condition. And then
18 even within that, you have another set of
19 circumstances to evaluate which is what is the
20 morbidity or immortality of the condition? What's
21 the severity of the condition if it does happen?
22 So I just want to point out that embedded
509
1 in Adil's point there are multiple points, you know,
2 none of which I think has been fleshed out in the
3 literature particularly, and I don't think that you
4 can really -- I mean, it seems to me that the
5 workgroup -- either the workgroup has to do it or
6 somebody has to do it, but if this research on
7 children is going to continue, somebody has to
8 grapple with those issues.
9 DR. MORENO: Alan, you'll be happy to know
10 that my comment actually follows Mark's.
11 I was going to suggest that if -- not
12 knowing whether this is the case or not, if the
13 advisory committee has the resources that we
14 commission a legal and a philosophical paper on the
15 question of the meaning of the concept of condition
16 and it's applicability. We are desperately in need
17 of some conceptual clarity on this and it could be so
18 critical to what you are doing and we are doing with
19 respect to kids that I actually think this is a very
20 high priority.
21 You asked the question whether there was
22 anybody around who had experience with the NBAC and
510
1 you didn't look at me which was very nice of you. In
2 fairness, I do want to say that the report that I
3 helped to draft on the role of persons with
4 diminished decisionmaking capacity in research was
5 not about children. It was specifically not about
6 children in research. And I did, and I think I can
7 prove it because I think it's still on my hard drive,
8 have a draft that included a minimal risk category
9 that was -- I'm sorry, a minor increment over a
10 minimal risk category and that was pegged to
11 examples, interestingly enough, examples that I
12 gleaned from various reports, the Alzheimer's group,
13 for example, had a task force that identified
14 specific examples of minor increment over minimal
15 risk procedures, the Tri-Council the Canadian Tri-
16 Council had examples that were almost identical -- a
17 lumbar puncture for example -- to those represented
18 in the Alzheimer's task force.
19 The Commission decided that as a manual
20 concept we are prisoners of our examples. And
21 therefore, that -- and this is something that we need
22 to worry about too, I think, even though we may
511
1 reject it ultimately, that IRBs will, feeling legally
2 driven in some cases, stick only to those examples
3 and not use them as guidance, but as hooks and be
4 constrained by them.
5 DR. FLEISCHMAN: Bob.
6 DR. R. LEVINE: Most of what I wanted to
7 say would have been in response to Elliot's question
8 that the way things are particularized to specific
9 diseases or conditions is not through changing the
10 standard of minimal risk, but rather to say that
11 there are additional justifications when there's a
12 minor increase and that is the knowledge you are
13 pursuing has to be of importance to understanding the
14 disease or condition that the child subjects have,
15 and also that the experiences must be commensurate
16 with those that they would expect in their actual, in
17 this case, medically defined situation.
18 This is why it's so important now to do
19 what Jonathan says about getting a definition of
20 condition because in people who are just predisposed
21 to have something, there is not yet anything that's
22 commensurate with their actual life experience. I
512
1 look forward to the paper that gets commissioned, if
2 it does, in clarifying this sort of thing.
3 I also want to agree most vigorously with
4 Alan's concern about the NBAC report. I think it was
5 a very serious error to omit the minor increase
6 category in the report on people with decisional
7 incapacity. I didn't know before that Jonathan had
8 proposed it be included, but I want to congratulate
9 you for that.
10 DR. MORENO: Thank you.
11 DR. FLEISCHMAN: Greg will be next. But
12 actually the report, I think, was on adults with
13 mental disorders.
14 No, I think that was an even better reason
15 to be opposed to that report; right.
16 DR. KOSKI: Well, actually, Bob already
17 made the point that I was going to make. But in the
18 sense of a more general comment, it seems to me that
19 it's as egregious to omit or exclude children from
20 research that would help us to understand
21 particularly those diseases and conditions that
22 affect them. It's just as egregious to exclude
513
1 pregnant women from research just because they happen
2 to be pregnant women, recognizing that there are
3 special situations that arise there. But there
4 clearly is a need to know about these disorders, you
5 know, how they develop and so on.
6 So I mean, we've already heard about the
7 problems of using drugs to treat children where we
8 don't really know how the drugs work in the children
9 and all that. Perhaps, you know, the notion of
10 actually treating diseases with those drugs that we
11 don't even understand either is a serious concern to
12 me.
13 So, you know, I say that not only as an
14 investigator, an IRB member, but as a parent and
15 everything else, we want to make sure that we
16 recognize in doing this that research has enormous
17 value and we just have to be certain as we're trying
18 to do that it's going to be done appropriately.
19 DR. FLEISCHMAN: I'm going to call on
20 Elliot and then I'm going to ask our liaison and
21 public members for comment specifically around these
22 issues about minimal risk, minor increment over
514
1 minimal risk, disorder and condition.
2 Elliot.
3 DR. DORFF: Just a note about defining
4 things, if we're interested in defining a condition.
5 Everybody would love to have what philosophers call a
6 "necessary and sufficient condition" to define
7 something. But there are very few -- once you get
8 out of the world of constructed worlds like
9 mathematics and logic, there are very few necessary
10 and sufficient conditions that exist. I mean, I can
11 give you one. A bachelor isn't a married man. Okay.
12 But that's about it.
13 And so then the question is, in the real
14 world, what do you mean by a definition. And the
15 entomology of the term coming from the Latin means
16 that you're drawing a boundary around something. So
17 part of the way that you come to a definition is that
18 you try to describe what's inside the things that
19 you're talking about and what's outside the things
20 that you're talking about.
21 Now, sometimes you can do that pretty
22 well. Even if you can't get to a necessary and
515
1 sufficient condition, you can try -- you can more or
2 less describe what a table is even though any given
3 definition that you give me I can show you something
4 that's not that, that's probably a table or something
5 that fits it that isn't a table, because that's just
6 the nature of things.
7 And you gave me functional definition or a
8 definition of native, you know, it's made up of
9 certain things or a formal definition has a certain
10 form or something on that order. And there will be
11 some very funny things that end up being called
12 tables by your definition and some things that you
13 think are tables that are not.
14 But, nevertheless, that kind of thing is
15 something that we more or less can define. When you
16 get to things much more complicated like an illness
17 or a condition, you may be able to give at least some
18 stabs at what it is. But maybe in the end the best
19 that you are going to be able to do is to give some
20 examples. Some examples of things that are indeed
21 the kinds of things you're talking about and some
22 things that are not the kinds of things you're
516
1 talking about.
2 The only reason why I'm making this point
3 is because if indeed we are going to be looking for a
4 definition of condition or disease, I think we
5 shouldn't deceive ourselves into thinking that that's
6 going to be very neat and clean in the end. That
7 somebody is going to come up with the definition.
8 They're going to say -- you know, and everything is
9 going to be wonderful in the world.
10 One of the things that you learn when you
11 go from philosophy 1A to philosophy 1B is that the
12 world doesn't live by philosophy.
13 DR. FLEISCHMAN: Thank you. Comments from
14 our liaison and public members about this area of the
15 discussion.
16 If you would come to the microphone and
17 identify yourself, Doctor.
18 DR. WILL: Ben Will from the NIH, although
19 I'm speaking just as myself, not representing anybody
20 in particular.
21 Actually, my comment really actually goes
22 back to the last comment by Elliot Dorff. I often
517
1 struggle with regulations and how to interpret them
2 and in the end what I often find myself doing, having
3 sat on IRBs for many hears is asking myself the
4 question of whether or not this research is ethically
5 acceptable and what was my intuition about whether
6 this is a sound research project or not. And we can
7 then attempt to figure out how the regulations work.
8 And I think there is some value to doing that
9 approach rather than just first trying to define each
10 of these terms, and I'll try to give you a couple of
11 examples of how this comes up.
12 I think that -- and I think the point I
13 want to make is I might be more willing to be more
14 relaxed on the definitions of minimal risks because
15 I'm concerned about the implications of putting too
16 much weight on the subjects of condition requirement
17 or on the prospect of direct benefit requirement.
18 I think the problems with the subject
19 condition requirement and putting a lot of weight on
20 that is that it then asks children to participate in
21 non-beneficial interventions precisely because they
22 have a disease. And I think that puts additional
518
1 burden on children with a disease. I think the
2 problem with the putting too much weight on the
3 prospect of direct benefit is that it only
4 contributes to the therapeutic misconception.
5 Now, just give me a moment to back up and
6 try to explain examples I'm talking about. I think
7 Phase I oncology research we all believe is
8 acceptable research to be done. That's research that
9 we couldn't even conceive of occurring in people who
10 did not have untreatable cancer. It would be
11 inconceivable to do that on children without that. I
12 think that's the example of where we want to think
13 about subject's condition and think about the risk of
14 that as being more than minimal risk, but because I
15 have this disease and it's a balanced situation, we
16 might accept that.
17 I wonder whether for other experiences
18 that involve non-beneficial research in children such
19 as conscious sedation which is an incredibly widely
20 used circumstance that while there are risks of that,
21 thinking of that as a minimal risk even though I
22 realize that may sound provocative, thinking of that
519
1 as a minimal risk intervention would allow us to
2 avoid only doing procedures involved in conscious
3 sedation on children with a disease or trying to
4 expand the notion of disease or condition very
5 broadly.
6 DR. FLEISCHMAN: Thank you.
7 Other comments from the committee or the
8 liaison and public members?
9 [No response.]
10 DR. FLEISCHMAN: Okay. then we're going
11 to move on to continuing our discussion through this
12 document. I'm going to skip to page 7 of this
13 document. Question 4, under the question from the
14 Congress, the definitions of direct benefit to the
15 individual subjects and generalizable knowledge about
16 the subject's disordering condition we have had some
17 of this conversation about condition and we want to,
18 in this area, talk about -- I'm sorry.
19 Oh, maybe they don't.
20 It's question No. 4 on page 7 is where I
21 am.
22 [Simultaneous conversation.]
520
1 DR. FLEISCHMAN: All right. I'm sorry. I
2 think we're reading from the same words. Are we
3 reading from the same words?
4 CHAIRPERSON MARSHALL: Yes.
5 CHAIRPERSON MARSHALL: But different
6 pages.
7 Okay. Since I've scribbled on this, I
8 will now not use the pages, but I will try to focus
9 us to where we are.
10 Okay. Does everybody have where we are?
11 We are under question 4, "The definitions of:"
12 Okay. What I'd like to do is take this
13 time to begin to talk about the -- there's a serious
14 question and problem with placebo controlled trials
15 which the workgroup gave a first look at. Because I
16 think this is one that's going to take more
17 conversation. And in that second paragraph the
18 workgroup said, in general, the use of a placebo
19 controlled trial is acceptable when it is not known
20 if a new therapy is beneficial and there is no
21 existing standard efficacious treatment. Such trials
22 examine both efficacy and toxicity of the active
521
1 treatment.
2 Even in the instance where there is a
3 standard treatment, the use of placebo controlled
4 trials can be ethical depending on the seriousness of
5 the disorder under study, the risks of the standard
6 treatment and the natural history of the disease.
7 The prospect of direct benefit to
8 individual subjects may be possible because a subject
9 might be randomized into the active arm or the
10 treatment. And that the treatment if proven
11 effective may be available in a crossover design or
12 at the end of the initial study.
13 Individual IRBs will need to review
14 placebo controlled protocols carefully, but may be
15 determine that some level of risk above minimal is
16 acceptable for the potential benefit of participating
17 in such a trial.
18 And there is a second part to this
19 conversation about placebos, and that is the part
20 about what constitutes a placebo. There has been a
21 lot of conversation in the child research ethics area
22 as to, for instance, the injection of a non-active
522
1 substance as a placebo as opposed to the injection of
2 an active substance and whether that's a level of
3 discomfort that is acceptable in a placebo controlled
4 trial for a child not receiving an active substance.
5 So there is consideration about this whole
6 issue. The workgroup does feel that placebo
7 controlled trials are ethically defensible in certain
8 specific circumstances and that controlled trials
9 might allow for certain types of placebo like even
10 injection in certain specific instances and that IRBs
11 would have some availability to determine this. But
12 these are, I think, very complex and difficult
13 decisions and this conversation, I think, needs to
14 open to the committee for some thoughtful comments.
15 Adil.
16 DR. SHAMOO: I have a simple one and then
17 later on after the other people talk I will ask
18 again.
19 The simple one is this, in the animal regs
20 they use the word "discomfort" and "pain" and I think
21 in the children's regs, whatever we are going to
22 write or draft, we should start talking about
523
1 discomfort and pain to children. Because I presume
2 we all agree, children are as valuable as animals and
3 animals has been in existence for 30 years, 40 years.
4 DR. FLEISCHMAN: Actually, the workgroup
5 has chosen to add an additional indignity so that in
6 the concept of risk would be both pain, discomfort,
7 and indignity. So that would, I think, even go
8 beyond what you're suggesting. That's the language
9 that the workgroup has chosen in the document.
10 Comments about placebo controlled trials.
11 Abbey.
12 MS. MEYERS: Well, this goes back to what
13 we were just talking about. Because if we're talking
14 about healthy children who aren't supposed to have
15 any risk or we're talking about, you know, absolute
16 minimal risk and we say that placebo controlled
17 trials are okay with healthy children in the placebo
18 group, then we're canceling out what we just said.
19 In other words, a child in a placebo group should
20 have the condition, it seems to me. Because then the
21 minor risks would be worth it.
22 But if you're going to study healthy
524
1 children and expose them to any of this, which is at
2 the very least emotionally upsetting, I don't think
3 they should be in a placebo group.
4 DR. FLEISCHMAN: Can you help me just to
5 understand your concern. You don't believe they
6 should be in the treatment group either.
7 MS. MEYERS: Healthy children?
8 DR. FLEISCHMAN: Well, that's right --
9 MS. MEYERS: Why would they be in this
10 study.
11 DR. FLEISCHMAN: -- but what I don't
12 understand is your -- generally, as I understand
13 placebo controlled trials, there's an active
14 substance and a non-active substance.
15 MS. MEYERS: Right.
16 DR. FLEISCHMAN: So if children were
17 healthy, they shouldn't be in either arm; right?
18 MS. MEYERS: Right.
19 DR. FLEISCHMAN: Okay. So I'm not sure
20 what the concern is.
21 MS. MEYERS: The concern is --
22 DR. FLEISCHMAN: A trial of an active
525
1 substance for children who don't have a problem
2 wouldn't be approved. So I'm not exactly sure what
3 the specific concern is.
4 MS. MEYERS: Well, what about that
5 diabetes trial and those children here at NIH which
6 the IRB approved.
7 DR. FLEISCHMAN: Exactly.
8 MS. MEYERS: They were healthy children.
9 Their only sin was that their parents were fat.
10 DR. FLEISCHMAN: Okay. Coming back to
11 that trial so just we're clear so we can focus the
12 conversation. My understanding was, that wasn't a
13 placebo controlled trial. That was a group of
14 children who had some studies done to look at a
15 predisposition to a problem and we may disagree about
16 whether that should have been done or not done. But
17 it wasn't a placebo controlled trial. It was a group
18 of children who were thought to have a predisposition
19 toward a problem and were studied in ways that you
20 may not think were appropriate.
21 MS. MEYERS: Any day of the week you could
22 pick up a newspaper, get on the subway and look at
526
1 the advertisements, call this telephone number to
2 volunteer to go into this clinical trial. They are
3 soliciting healthy people, adults and children all
4 the time, especially children now because the
5 pediatric exclusivity thing. And they're looking for
6 healthy people. Even if they're going to study cold
7 medicines, or flu medicines, or whatever, healthy
8 children are being studied and given placebo and
9 active substance.
10 DR. FLEISCHMAN: Bob.
11 DR. R. LEVINE: Abbey, I wanted to respond
12 earlier when you brought up the example of using
13 healthy children as controls for a placebo controlled
14 trial of antibiotics. I can't imagine that any
15 scientist would propose to do that, and I can't
16 imagine that any funding agency would agree to fund
17 it, and I can't imagine that any IRB would approve
18 it. When you do a placebo controlled trial of a new
19 treatment, it doesn't make sense unless all the
20 subjects have the disease or condition you're trying
21 to treat.
22 The fact that we see posters in subways is
527
1 a little distressing. But they're not inviting
2 healthy people to come in for placebo controlled
3 trials. They may be inviting them to come in for
4 studies in basic physiology, but usually they don't
5 go to the expense of posting those in subways because
6 they can find a lot of them around the university.
7 I want to address what's in the paragraph
8 of the working group's report. I think the standard
9 for justification of placebo control, what you have
10 done is you've eliminated one category as being
11 ethically problematic and that's put in terms of
12 depending on the seriousness of the disorder.
13 What you then leave is how do you justify
14 the other placebo controls. And what you've done is
15 tried to squeeze placebo under the rubric of
16 therapeutic because there's a chance to get
17 randomized to get something else.
18 If you take seriously the clinical
19 equipoise justification of a clinical trial, if you
20 can say convincingly that the active agent that
21 you're evaluating is at the outset not known to be
22 better or worse than placebo, then you have basically
528
1 what you're arguing at the outset is that as far as
2 you know, this will be the equivalent of an inert
3 substance. They may both be non-therapeutic. But I
4 think what you're hoping for is that the active
5 substance will be effective.
6 I think a way to articulate the standard,
7 coming out with nearly the same results is that the
8 primary justification of placebo is that withholding
9 of known effective therapy for that condition will
10 not, in and of itself, result in any serious risk of
11 an adverse consequence.
12 What this permits then is let's say, if
13 you want to look at a new treatment for allergic
14 rhinitis, you can say, there are 100 treatments out
15 there, but we want to see whether or not this one has
16 efficacy. If you withhold one of those hundreds of
17 treatments for allergic rhinitis, the worst you
18 expose the patient to is transient runny nose.
19 If you say to the parent and the child, at
20 any time the child can say, "I want out of this"; you
21 say, "why do you want out of it?" Because I want
22 treatment. I want relief of my runny nose. Now,
529
1 you've got an outcome measure of the trial. This is
2 a way it's commonly done.
3 The standard though, I think, has to be
4 you can't withhold any effective therapy when such
5 withholding plausibly presents a risk of a serious
6 adverse consequence. The serious adverse consequence
7 could be prolonged discomfort. I mean, you don't
8 have to die to call it serious.
9 And that's the way I would like to see the
10 standard written. Thank you.
11 DR. FLEISCHMAN: Sandy.
12 DR. CHODOSH: Actually, I want to get back
13 to something that is being misinterpreted, I think as
14 a placebo. There are instances where an antibiotic
15 indeed may be given to a healthy child. If you were
16 trying to figure out the pharmacokinetics and the
17 toxicity in the early stages and what the dose should
18 be, that is the way that it's normally done. I had
19 to say that I would oppose that. I've always opposed
20 it. My feeling is that those Phase I trials should
21 be done to people who have the illness on which that
22 drug is going to be used.
530
1 The FDA has taken a different point of
2 view. That until you know the normal, quote
3 "pharmacokinetics in normal people" then you can
4 evaluate whether it's different in sick people.
5 That's not the way it's developed over the
6 years. By and large Phase I studies in adults have
7 gone on to show that they're fine in healthy people,
8 but then they really repeat them in the sick people
9 that really need the drug. So you don't always know
10 that difference. But don't confuse the two. There
11 is a place at some point probably for doing or giving
12 a healthy child a drug that it will need. Because
13 you need, at some point, to figure out what is the
14 proper dose. Then you go on. It's not a placebo.
15 No placebo in there.
16 DR. FLEISCHMAN: And, Sandy, I'm going to
17 ask to hold that because that's precisely what we are
18 going to talk about in about eight minutes, and that
19 is the Phase I trials both in oncologic studies with
20 seriously ill children and then pharmacokinetic
21 studies with children not as seriously ill.
22 DR. CHODOSH: The only reason I brought it
531
1 up now is that Abbey mentioned use of antibiotics --
2 DR. FLEISCHMAN: No, no, that's very
3 helpful. But what I don't want is to move us now
4 into that -- to maintain your help -- no, to maintain
5 your help of not confusing us, we are going to stay
6 with placebo controlled trials and Bob's definitional
7 and justification comments was very helpful.
8 Any other comments from the committee
9 about placebo controlled trials?
10 [No response.]
11 DR. FLEISCHMAN: Any comments from our
12 liaison or public members about placebo controlled
13 trials?
14 Sandy.
15 DR. CHODOSH: I'll pipe in on placebo
16 controlled trials in that that is that something
17 again has happened by and large in drug development
18 which is a little bit disturbing. And that is the
19 fact that placebo are not always used in mild
20 disease, like in allergic rhinitis say, in which we
21 are showing quotes, "equivalence to drugs that are on
22 the market." You go down the road and after about 15
532
1 such pairings, and new drugs, that you really don't
2 know that that drug that was developed for the 15th
3 time is really any good at all. Because the others
4 really have never been exposed to the true situation
5 of no therapy at all. It happens in antibiotics.
6 There are a lot of situation in which this is
7 occurring. And the FDA allowance of equivalence or
8 accepting equivalent type studies, there are places
9 where placebo really would make a difference,
10 although not in the antibiotics studies, I don't
11 think.
12 DR. FLEISCHMAN: Actually, that's a very,
13 very important comment because one of the members of
14 the workgroup who is a national expert in otitis
15 media antibiotic trials argued that he has been told
16 it's unethical to develop a placebo controlled trial
17 around the treatment of otitis media in children
18 because there is, quote, "known efficacious treatment
19 for otitis media in children." When one unpacks that
20 argument there is very little that was ever done that
21 created the thought that there was no efficacious
22 treatment for otitis media, but is certainly the
533
1 standard of care.
2 Now, when people are beginning to question
3 that and look carefully at that question and want to
4 do placebo controlled trials it becomes very
5 difficult. So, he for one was really quite vocal
6 about the critical importance of placebo controlled
7 trials early on in studies and the problem of
8 efficacy trials as you've pointed them out.
9 Greg.
10 DR. KOSKI: Well, it probably doesn't need
11 to be said, but I will anyway, that in many
12 instances, placebo responses can be so dramatic that
13 in fact they outreached the actual therapeutic
14 responses to medications that are being given. And
15 we see this particularly in trials that may often
16 affect the children population because of the use of
17 pharmacologic agents for treating behavioral, and
18 tensional disorders and so on.
19 So, again, I think we need to be very
20 careful as we pointed out in the discussion of the
21 declaration of Helsinki yesterday, not to simply have
22 a blanket prescription against placebo, but to
534
1 recognize that placebo is a very critical part of the
2 scientific approach to determining whether or not
3 drugs are truly safe and effective and we need to
4 recognize their appropriate use as well as their
5 inappropriate use.
6 DR. FLEISCHMAN: Judith and then Bob.
7 DR. SIEGEL: I was just going to actually
8 bring that up. I mean, when you're looking at risk
9 assessments and you look at the number of patients,
10 for instance, you have to include in the trial that's
11 an equivalency trial versus the number of patients
12 you actually may have to treat in the placebo
13 controlled trial, you will find that the population
14 that you put at risk in the first place is much less
15 in a placebo controlled trial.
16 And, again, speaking to the opposite, if
17 you go with those kinds of definitions that talk
18 about increases of diseases that there will be no
19 increase in, for instance, morbidity and mortality
20 and look at those as the kind of trials that you
21 might want to go in with less patients at first than
22 going right into an equivalency trial, then you start
535
1 to get a much better, I think, look at the relative
2 risks of doing this type of research using placebos
3 particularly.
4 DR. FLEISCHMAN: Bob.
5 DR. R. LEVINE: Now that it appears that
6 we've turned it all around and everybody's speaking
7 in favor of placebos, I want to take a little bit of
8 it back. There were stories in the media a month or
9 so ago about a proposal to conduct a placebo
10 controlled trial of a human surfactant in newborn
11 infants. And the justification for this was that the
12 non-human surfactant preparations had been evaluated
13 in pediatric or neonatal intensive care units ten
14 years ago or more and that the state-of-the-art in
15 running an intensive care unit for neonates had
16 changed dramatically. And so at this point it would
17 be unclear if there was an equivalency or a non-
18 inferiority trial.
19 It would be unclear as to how much of the
20 good effect would be due to the changed condition in
21 the intensive care unit and how much of it would
22 actually be due to the new human peptide C surfactant
536
1 preparation.
2 I think that before our comments could be
3 taken to mean that we would ratify that sort of
4 trial, I would have to say that before we could do
5 that, there would have to be considerable discussion
6 within this group. As to whether or not the change
7 in the state-of-the-art intensive care units would
8 invalidate equivalents or non-inferiority trials,
9 particularly when there is evidence that the old
10 surfactant does seem to prevent very serious adverse
11 consequences in at least some of the children. Thank
12 you.
13 DR. FLEISCHMAN: Adil.
14 DR. SHAMOO: I have a question. When are
15 we going to discuss putting real serious drugs for
16 the first time on healthy children. That's really
17 the issue I want. When is it going to come out. Is
18 it going to come out in Phase I studies, or are you
19 saying your working group have eliminated and we will
20 never do a drug for the first time in healthy
21 children? Isn't that Phase I that's going to come
22 up?
537
1 DR. FLEISCHMAN: I think so.
2 DR. SHAMOO: Okay. I'll wait.
3 DR. FLEISCHMAN: And if it doesn't then
4 we'll have to take it up in addition.
5 DR. SHAMOO: I will wait and the placebo
6 is something that there's a consensus -- no, there is
7 no consensus. At least I for one will say I do not
8 agree with all the type of placebo unless they are
9 under unique or compelling circumstances rather than
10 blanket statement, "no placebo"; that's ludicrous to
11 have any blanket statement, absolute statement.
12 But the way we are using it now, we have
13 opened the door such that I think you could do almost
14 a lot of experiment which were not done -- they were
15 not supposed to have been done with the previous even
16 ranks. They pushed a lot of category four, I call
17 them "category four"; you call them, I think category
18 407. They pushed them to mean 406. IRB pushed them
19 to mean 406 even though they are 407.
20 The fenfluramine experiment, for example,
21 which you are very aware of since you lived in New
22 York City, that was 406 by the way, it was not a 407.
538
1 That was not the category where you have to go all
2 the way to the Secretary in public hearing. They
3 basically camouflaged the direct medical benefit,
4 they camouflaged the risks, and to me personally I
5 don't believe fenfluramine is a low-risk drug to be
6 taken. And that was known 15 years before the
7 experiment.
8 DR. FLEISCHMAN: Abbey.
9 MS. MEYERS: I just want to say that
10 whatever your committee does on this section about
11 placebos, it has to be in concert with the last
12 section that we talked about because there it says
13 that healthy children cannot be experimented --
14 participate in clinical trials. Here it says that
15 they can and the two sections are very confusing.
16 And, you know, placebos, nobody -- I don't
17 think there's anybody who knows anything about
18 science who is going to say placebos are bad and
19 should be outlawed. Everybody understands the
20 importance of placebos. But I don't think in many
21 cases that some of these trials have been approved
22 with truly ethical standards. And, in fact, in many
539
1 cases if there was another standard therapy, it
2 should have been compared against that.
3 In the case of the surfactant, they should
4 have compared some of the babies with the old
5 surfactant to some of the babies with the new
6 surfactant instead of saying, "let's put some of them
7 on placebo" which means death.
8 So I think a lot of these decisions are
9 being made now even in the context of all the new
10 awareness about bioethics. They're being approved in
11 ways that are unethical.
12 DR. KOSKI: I don't think it would be fair
13 to leave the impression that the surfactant trial in
14 question was ever done. It was not done.
15 DR. FLEISCHMAN: And I think, Abbey, Bob
16 was agreeing with you to say that that surfactant
17 trial, as he described it, ought not have been done
18 and it wasn't. Uh-oh.
19 DR. R. LEVINE: No, I'm sorry. That would
20 presume more knowledge of the trial than I have.
21 What I said is I would not want what we're talking
22 about to be extended to cover something of that sort
540
1 without a lot more further discussion.
2 DR. FLEISCHMAN: Okay. And I don't think
3 the working group had any intention of this paragraph
4 covering that sort of trial. And if we need to be
5 more clear on that, we can be.
6 Susan.
7 MS. KORNETSKY: As a person who sits on an
8 IRB that reviews a lot of randomized placebo trials
9 with children, one of the things that I think IRBs
10 practically struggle with is, which is alluded to in
11 here, and I'm interested in people's opinions not
12 necessarily from the working group is the discussion
13 here that in the placebo arm might receive the
14 potential for direct benefits. I think a lot of IRBs
15 struggle with that and whether there is a potential
16 for direct benefit.
17 What's written here which is frequently
18 used as justification is that they might be able to
19 -- they might be randomized into the ARM, or they
20 might be able to receive it as a crossover at the end
21 of the trial which isn't necessarily always true.
22 And we've come up against that because many times
541
1 that is used as a justification.
2 So, I guess, you know, I have my own views
3 about this which I'll -- you know, but I guess that's
4 where I feel IRBs sometimes really struggle is in a
5 placebo arm, can you make the justification that
6 there might be a potential for direct benefit.
7 DR. FLEISCHMAN: I think it will be very
8 helpful for the committee as well as others to give
9 comments to the working group very specifically about
10 this issue and as Susan is describing it, and as Bob
11 has described it, the justification for what most
12 people think in some circumstances is appropriate and
13 permissible research.
14 Did I have Mark's hand up or not? No.
15 Sandy? And then we're going to on to our
16 fourth -- after Elliot we're going to go on to our
17 fourth item.
18 DR. CHODOSH: What I heard from Adil sort
19 of bothered me. And that is that he has now presumed
20 that this group has come out saying that placebo
21 studies are fine everywhere and that is not the case.
22 That nothing that I said should presume that and I
542
1 would hesitate to have that be passed on as if that
2 were what the committee --
3 DR. SHAMOO: I did not --
4 DR. CHODOSH: You did say that.
5 DR. SHAMOO: No, I said, Bob.
6 [Laughter.]
7 DR. FLEISCHMAN: I think what I took as
8 Adil's comment was that we have some work to do in
9 justifying, clarifying in this area and I think that
10 the workgroup is quite comfortable in receiving that
11 input.
12 Elliot.
13 DR. DORFF: Susan, what would happen if
14 the rationale that you just described for placebo
15 studies were actually written into the conditions of
16 the study? In other words, that it wasn't just that
17 people approved such studies on the hope that other
18 could be crossover use of it or something on that
19 order, but that that it would actually be written
20 into it. I don't know enough about this stuff to
21 know what would happen.
22 DR. FLEISCHMAN: Susan.
543
1 MS. KORNETSKY: Well, I think, I mean, in
2 a very practical sense we really sort of struggle
3 with this issue of potential for benefit in the
4 placebo arm where, you know, in adult studies you
5 don't -- obviously you need to review the protocol,
6 but you're not -- you don't have to categorize
7 different things. So, I mean, I really think that's
8 the crux of the matter here and we've done some
9 talking around it, but that's the thing.
10 I mean, we try and write those things in.
11 You know, we've often asked for availability of drug
12 at the end of the trial. We've asked for questions,
13 can this be done as a crossover, and sometimes its
14 just not possible. And so you're really stuck with a
15 group of children with a condition or disorder, I'm
16 not talking about normal children, who you know are
17 not -- you know, have a 50 or, you know, however it's
18 stratified, you know, percent and is that
19 appropriate.
20 DR. FLEISCHMAN: Elliot, I have sat on two
21 IRBs that have demanded it be written into trials or
22 not allowed such studies to go forward. So IRBs have
544
1 the authority to do what you're suggesting.
2 Sometimes it's complex because they're hopeful and
3 the pharmaceutical company will not agree and yet the
4 investigators and the families even want such a
5 trial. So it becomes a difficult issue for the IRB,
6 but it is possible to reject such a study unless it
7 is designed in ways that are ethically acceptable.
8 MS. KORNETSKY: We have rejected them and
9 we've required changes and I think we've, you know,
10 done different things. And you have to take a lot of
11 other things -- I don't think you can sort of say
12 standardly what you should or shouldn't do. You have
13 to take everything into context.
14 DR. DORFF: Right. But it seems clear to
15 me from this conversation that if you could indeed
16 insist on that, then people would feel much better
17 about placebo studies, ethically, because then you
18 would be able to say that if the drug does indeed
19 prove to be effective that the people who were not
20 given the drug would then get it retroactively, or at
21 least to the extent that it could be.
22 Now, if I've got this completely wrong,
545
1 which I think I have -- the faces that I'm seeing --
2 then fine, then tell me. But the point is that if
3 that is true, then even if we couldn't demand it as a
4 standard, then we could say that IRBs ought to aim
5 toward that.
6 DR. FLEISCHMAN: Greg.
7 DR. KOSKI: Well, it's important to
8 recognize that when you're developing a new drug,
9 there's potential benefits and there's potential
10 risks. So requiring that a child be given the
11 opportunity to be exposed to the potential risk is
12 something that you might want to think twice about
13 because it's a double-edged sword.
14 The likelihood that any given drug is
15 going to be shown to be safe and effective in one
16 trial is essentially zero. Now, it happens, perhaps,
17 in some rare occasions that a drug will be that
18 dramatic. But, in fact, we need to be very careful
19 about it. So the -- you know, the thoughtful
20 exercise of reasoned judgment in each of these cases
21 is something that you really have to strive for and
22 it's very hard to achieve that through a blanket
546
1 statement that you have to require the active drug
2 afterwards. It's complicated.
3 DR. FLEISCHMAN: I have on the list, Bob,
4 Judith, Adil and Susan.
5 DR. R. LEVINE: I think the most recent
6 discussion underscores the reasons for my
7 recommendation that justification of placebo be
8 evaluated in terms of whether withholding known
9 partially affected therapy could result in a serious
10 adverse consequence. If it could, then a crossover
11 design doesn't help you. It just means that you're
12 exposed to the possibility of a serious adverse
13 consequences for half of your time in the trial. But
14 everybody then gets exposed to that possibility.
15 And giving the drug after the trial is
16 over is a good idea, but it still doesn't mitigate
17 the problem of placebo controls. If there's going to
18 be an exposure to a possibility of a serious adverse
19 consequence, then you've got a big problem with
20 ethical justification. Depending on how serious the
21 consequence is, it might rise way above the threshold
22 of a minor increase above minimal risk.
547
1 DR. FLEISCHMAN: Judith.
2 DR. SIEGEL: I wanted to comment on the
3 question of, is there any benefit or potential
4 benefit in a placebo controlled trial. There is
5 quite a large literature on placebo controls and the
6 whole issue of placebo effects.
7 And I think the question is, can you say
8 that the effect you get on drug X for instance, and
9 if you get the same percent response, let's say, on
10 placebo as you get on drug X, does that qualify as a
11 therapeutic response. And, again, in many trials the
12 way you evaluate it, placebo and your drug look
13 exactly the same.
14 Now, can say that there is no effect of
15 the drug. Or, is a 30 percent or a 40 percent, or a
16 50 percent placebo response which is also not
17 uncommon in certain areas, equal to the effect --
18 some effect.
19 Now, clearly if you have a 50 percent
20 placebo response rate, you are looking for a drug
21 that can actually do much better, but can you say in
22 those trials that there has been no benefit. And I
548
1 would suggest that possibly during the deliberations
2 of this a review of placebo response that you can
3 find in the literature might be helpful.
4 DR. FLEISCHMAN: Thank you. Adil.
5 DR. SHAMOO: [Off mic.] I think there is
6 a great deal of placebo design that is done because
7 it's cheap and fast. And we are all not talking
8 about that. But that's really the reason because you
9 can get statistical data faster and cheaper in a
10 smaller number of patients, et cetera, et cetera. I
11 don't want to go there.
12 Let's go over this following scenario.
13 You have children who have an illness and you put 100
14 of them on placebo for one year and 100 on the new
15 drug. But it is a slow progressive disease, but you
16 don't know that, and let me give you the outcome, for
17 example. That after the one year, and I will even
18 take Elliot Dorff's example, you are so kind that you
19 gave the medicine to those children whom they were on
20 placebo after one year. You find out that after you
21 give them the drug they never reach at all the same
22 therapeutic outcome as those who were on drug
549
1 therapy.
2 My question to you is, how would you
3 handle a scenario like that in your placebo? And
4 that's not farfetched.
5 DR. FLEISCHMAN: No, no, this is
6 absolutely critically important to children what
7 you're saying. If you'll drop your microphone for a
8 moment.
9 We have to suggest that those 200 children
10 have a disease for which there is no known
11 efficacious treatment. A placebo controlled trial
12 has now determined, over the course of a year, that
13 there is efficacious treatment to slow down this
14 progressive disorder. The 100 children who have been
15 randomized into the non-active substance group now
16 given the substance have not had the benefit of the
17 earlier treatment, but we didn't know that it was
18 effective.
19 So we now know it's effective, so all
20 future children, theoretically, could now be given
21 such a treatment and these children who were in the
22 placebo arm have benefitted all of the children with
550
1 this disorder now and forever and they've also maybe
2 slowed down their process, but not as dramatically as
3 it would have been if they got into the active arm.
4 But the key here from the ethical analysis
5 of whether a placebo controlled trial was appropriate
6 is that we had no knowledge of what we now have
7 knowledge about a year later.
8 DR. SHAMOO: But you are assuming that
9 there was zero current existing efficacious medicine.
10 Let's assume the slowing down of the illness, there
11 was medicine which is not as good, 20 percent or 30
12 percent.
13 DR. FLEISCHMAN: Well, that then changes
14 the IRB assessment as to whether a placebo controlled
15 trial is appropriate.
16 Bob I think helped us --
17 DR. SHAMOO: No placebo control is that
18 what you're telling me? There will be no placebo
19 control.
20 DR. FLEISCHMAN: Well, you know, the devil
21 is in the details, Adil. Bob explained, I think,
22 very nicely that justification has to do with the
551
1 ability to withhold or withdraw a treatment without a
2 serious negative consequence. That allows then,
3 based on knowing the natural history of the disorder,
4 knowing the disease, it allows an IRB to assess in
5 what circumstances a placebo controlled trial might
6 be appropriate and conversely in what circumstances
7 it would not be appropriate. But that's often going
8 to be a judgment call based in assessing those facts.
9 Now, that's why you and I both agree we
10 need review of IRBs and accountability so we can look
11 at how they're making those judgment calls over time.
12 And we need methods for assessing that, not in a
13 punitive manner, but in an important prospective
14 educational manner. But that's separate from the
15 issue of what is an ethically defensible placebo
16 controlled trial.
17 Greg.
18 DR. KOSKI: There's an article that was
19 written by Bob Temple and Susan Ellenberg that is, I
20 believe in JAMA. I don't know the exact reference.
21 Where is it? Oh, that's right. In the Anals of
22 Journal Medicine. That is well worth reading for
552
1 people who want to learn everything about placebo
2 controlled trials.
3 But, Elliot, you mentioned that placebo
4 controlled trials are, you know, faster and cheaper.
5 There may often be some truth to that. That's not
6 necessarily bad. In fact, the demonstrating quickly
7 that a drug is, you know, clearly scientifically
8 better than an existing therapy or that actually is
9 safe and effective is part of the strategy for
10 effectively minimizing risks to the numbers of
11 participants. And we could, perhaps, leave ourselves
12 in a position of subjecting individuals to, you know,
13 years of no treatment through the lack of development
14 of an effective drug.
15 And, again, I'm saying this not to
16 abdicate, you know, for, you know, doing unethical
17 research in any population, but to again point out
18 that we need to be very careful about how we consider
19 the role of placebo and not jump to conclusions that
20 would take us down a path that we wouldn't want to
21 get to. Because clearly we want to make sure that we
22 can reap the benefits of research appropriately.
553
1 And, as I keep saying, do it in such a way that we'll
2 be proud of the result that we get in the end. So
3 it's a difficult problem.
4 DR. FLEISCHMAN: Okay. Let me just tell
5 you where we're at in terms of the time and the
6 process. For those of you who came as guests this
7 morning, the children's discussion is going to
8 continue for a short time after lunch. And I
9 apologize if that's a problem for you. Because we
10 didn't want you to have that problem, but it has had,
11 I think, a very fruitful discussion. We have a part
12 that our chairperson has allowed us to put over until
13 after lunch.
14 So what I'm going to ask is, Elliot and
15 Sandy to make their comments and then we're going to
16 adjourn for lunch and return at an appropriate time
17 that Mary Faith is going to tell us about.
18 Let's have the two comments and then we'll
19 give the microphone to Mary Faith.
20 DR. DORFF: It just strikes me that this
21 particular piece of your report, Alan, is it seems to
22 me applicable to adults as well. I mean, except for
554
1 the issue of, you know, talking about assent and
2 concent and that kind of stuff which is a separate
3 issue. The issue of placebo studies and the kind of
4 criterion that Bob is suggesting, I think would be
5 true for adults as well.
6 DR. FLEISCHMAN: I think the
7 justifications of placebo controlled trials, the same
8 justifications hold. And I agree with you. But
9 because of the surrogate decisionmaking process, we
10 tend to allow adults to consider these issues more
11 carefully or themselves and make autonomous choices.
12 So it's an even more complex issue in the child area.
13 If we can get through it in the child area, then the
14 adult people, as is usually the case, will benefit
15 greatly from the children learning about these
16 things.
17 Sandy.
18 DR. CHODOSH: I have to go back to the
19 example that Adil mentioned and that is where there
20 is no other therapy that's been known, and therefore,
21 they go in a placebo. And you did not consider the
22 other possibility, that is, that the drug causes
555
1 harm. And that you would find this out very quickly
2 and that you would not expose additional people to
3 this drug and it would stop that research. And
4 believe me, there are many drugs like that out there
5 that you never hear about that you need to find that
6 out. And if you don't find that out, you could go on
7 forever giving toxic drugs to people.
8 DR. SHAMOO: Quick answer to Sandy. And
9 that is, we haven't talked, Alan, at all at what
10 stage of drug development are we going to use
11 children. We haven't talked about whether there is
12 -- what extent of animal study, what extent of adult
13 study, before we start injecting them into children.
14 We haven't talked about that.
15 DR. FLEISCHMAN: Actually, the workgroup
16 in its preliminary comments does make the comment,
17 and I agree with you, I haven't said that here. The
18 workgroup makes the comment of the obligation to look
19 at medications and other interventions in animals and
20 adults when appropriate before children.
21 Of course, there are children-specific
22 diseases like prematurity that requires interventions
556
1 with drugs without adult trials like the surfactant
2 trials. But, indeed, the workgroup agrees with that.
3 It has been the practice, it is the general approach
4 and we should make that clear.
5 I'm going to now ask Mary Faith to direct
6 us.
7 CHAIRPERSON MARSHALL: What we would like
8 to do is adjourn for lunch now and ask that we
9 readjourn early, at 1:00 -- reconvene, thank you.
10 Rita Colwell has had a delay because of
11 her flight this morning. But she is going to join us
12 after we reconvene at 1:00. So I realize we've taken
13 some of your lunchtime, but we've had a fruitful
14 discussion and we want to continue to do that.
15 I would just like to make the observation
16 that this particular discussion about placebo and
17 assessing risk and benefit really does beg the
18 question of ongoing monitoring as a procedural
19 safeguard during the trial which is something that we
20 have spoken to as well. And I think that this really
21 does show the need for that.
22 So we will see you back here at 1:00.
557
1 [Whereupon, at 12:05 p.m., the meeting was
2 recessed to be reconvened this same day at 1:00 p.m.]
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1 A F T E R N O O N S E S S I O N
2 [Time noted: 1:15 p.m.]
3 CHAIRPERSON MARSHALL: Shall we begin?
4 I know that we will have folks wandering
5 in and we have been on a tight schedule, but I want
6 to make sure that we have all the time that we need
7 for our ongoing discussion of children, and our
8 discussion this afternoon about social and behavioral
9 sciences, and also to take care of some housekeeping
10 issues, and to recap what we've done over the course
11 of the past two days, and to get you all home on
12 time.
13 Dr. Rita Colwell, who is the director of
14 the National Science Foundation is with us this
15 afternoon. We are delighted and honored to have you
16 to speak to us about the National Science Foundation
17 and research ethics. And perhaps she may have a
18 moment or two to have a conversation with us, if
19 there are people who have questions.
20 DR. COLWELL: Thank you very much, Mary
21 Faith and also Greg. I appreciate the opportunity to
22 be here and apologize for being late. But flying out
559
1 of Boston is not always easy.
2 [Laughter.]
3 DR. COLWELL: I thought I would get some
4 good response on that. I must say it was a lot
5 easier than the flight back for LaGuardia two weeks
6 ago when we emergency landed in Newark. I don't
7 recommend that. Newark is not exactly a tourist
8 place, especially in an emergency.
9 I am delighted to be here today to talk to
10 you about a really very important subject that you've
11 been focused on, and that is, human research
12 protections.
13 Let me begin by saying how much we value
14 our work at NSF with you in NHRPAC. Because
15 providing safe and ethical and equitable treatment to
16 human participants in research is -- well, it's an
17 undertaking of the very highest of importance. At
18 the National Science Foundation we put it at the very
19 top of our priority list.
20 Now, there is no question that the work of
21 this Committee is vital. I don't have to tell you
22 that, you know that. And it's also evidenced by the
560
1 very good public interest as well.
2 Those who participate in our research
3 deserve our highest respect. They are the unsung
4 heroes of the nation's research enterprise. We
5 simply couldn't do our work without them and when we
6 think back 50 or 75 years ago, the situations that
7 involved human subjects, we realize we've come a long
8 way, but we still have a way to go.
9 Taking the human subjects seriously as
10 partners, exercising vigilance over their treatment
11 are absolutely necessary if we are going to sustain
12 the public's trust in this enterprise.
13 I would like to add that Greg Koski's
14 office has been extremely helpful in this process of
15 clinical assessment and we appreciate that, Greg.
16 We've been able to share our perspectives
17 of these issues with Greg and his staff and I know
18 that we'll continue to do that in future. I think it
19 will be useful to talk to you today about the
20 National Science Foundation and the ways in which
21 people involved in our research enter into our
22 activities.
561
1 First let me begin with a few words about
2 my own research experience. I'm a microbiologist by
3 training. I evolved into becoming a molecular
4 biologist. For many years my research has focused on
5 cholera. It's largely controlled in the United
6 States, but it's a devastating presence in the rest
7 of the world. It's endemic in Bangladesh, for
8 example, where I've done most of my research over the
9 last 25 years. As my colleagues and I have
10 researched this disease, cholera, over the years, we
11 have had occasion to involve people in our research,
12 and in fact, we have a study underway right now with
13 about 52,000 people in 50 villages.
14 We've worked with human volunteers in our
15 study carried out at the University of Maryland
16 Medical School with the Center for Vaccine
17 Development. And that's an example of the kind of
18 clinical research, field research and clinical
19 research involving human subjects. But it's the
20 clinical research that usually comes to mind when we
21 consider safeguards for those involved in our
22 research.
562
1 It's usually the focus of our discussions
2 about human research protection and many of the
3 mechanisms that are in place to protect humans in
4 research take their cue for this particular model,
5 the clinical model.
6 Now, our cholera research has involved a
7 number of epidemiological studies which is another
8 quite different instance of research involving human
9 beings. In this case, we ask people to share
10 information about their health, their personnel
11 characteristics to help us understand the
12 distribution of disease in order to prevent and
13 control it.
14 Now, we have outreach workers who are part
15 of sort of an extension team working in the villages.
16 Our concerns in this kind of study focus on keeping
17 that information confidential and protecting the
18 individual's privacy. And making sure the
19 individuals are participating voluntarily and
20 understand what the experiments are about.
21 Now, my third and final example requires a
22 bit of background, if you will bear with me.
563
1 Filtration and chlorination of drinking
2 water is the best method for controlling cholera; no
3 question about it. We had cholera in Washington,
4 D.C., New York, Philadelphia, and Boston at the turn
5 of the century. In fact, not only cholera, but
6 yellow fever and a few other things. Washington was
7 called a miasmic swamp in those days. We might still
8 call it a miasmic swamp.
9 [Laughter.]
10 DR. COLWELL: For different reasons.
11 Filtration and chlorination of drinking
12 water is just not yet possible on a massive scale for
13 the Bangladeshi population. If any of you have
14 visited there, you will understand exactly what I'm
15 saying. And so we chose to test whether a simple
16 filtration, through inexpensive surrey cloth folded
17 four to eight times would alleviate the problem. We
18 found that it removed 99 percent of the cholera
19 vibrios from the water because they are associated
20 with zooplankton and they attach to the surfaces that
21 are in the gut, zooplankton, and they also attach in
22 a particular manner particularly to the remnants of
564
1 ecdyses as the zooplankton metamorphose.
2 That led to a sociological study to see if
3 this would be culturally acceptable. Indeed, it is.
4 We were told that the men would not drink water that
5 had been passed through the unclean cloth worn by
6 women. Well, it turned out to be nonsense. We had
7 been using it to strain yogurt anyway before they
8 drank it. So it was culturally acceptable. But it
9 involved a proper study with sociologists,
10 professionals, and our private team.
11 So now we are in the process of
12 determining whether with this very simple technology
13 we can reduce the incidence of cholera. And so we
14 ask people in these villages to provide us with
15 information about their social, their cultural lives,
16 or to let us observe them as they go about their
17 daily activities collecting the water, bringing it to
18 the household, feeding the children, washing
19 vegetables and so forth. That's another way in which
20 we engage humans in our research.
21 Well, I've taken you on this brief journey
22 and I don't think it's unfamiliar to you. But it
565
1 illustrates an important and sometimes neglected
2 truth. Scientific research involves and engages
3 human participants in many different ways and on many
4 different levels.
5 The studies differ substantially in the
6 risks they pose to individuals. Some may pose very
7 little risk in the case of surrey cloth there's very
8 little risk in using it; we hope to prove that there
9 will be a lot of risk in not using it. But it
10 requires extra vigilance to ensure confidentiality
11 and privacy because the kind of records we keep in
12 Matlab if any of you are familiar with that, studied
13 the village that has been in operation for, I think,
14 40 years and the data are extraordinary; everything
15 from illnesses, onset of puberty, onset of menses,
16 numbers of children, illnesses and the degree of
17 illness and so forth.
18 These kinds of -- this kind of information
19 may have consequences for the social and cultural
20 lives of communities and they raise broader concerns
21 about the source of consent or whether our research
22 may alter what we've set out to understand. Just as
566
1 an example, we have to be very careful to have a
2 buffer between villages because there is exchange of
3 information and obviously if the filter works very
4 dramatically others will use it and the experimental
5 results get confounded.
6 But there's also the very difficult
7 decision that if it becomes dramatically successful,
8 when do you stop the study and begin to implement it
9 for everybody?
10 So it's not news that human arrangements
11 are complex. It isn't surprising that accommodating
12 them in our research, while maintaining our
13 responsibility to those who participate, is a huge
14 task. It's going to require all the creativity and
15 subtly that we can muster and I'm absolutely
16 certainly that this forum is up to the task.
17 There are some other considerations that
18 make our work on these issues timely. The research
19 enterprise itself is changing. We have to be
20 flexible and agile so that we can adapt to these
21 changes. Let me explain what I mean by this.
22 Today advances in science and technology
567
1 are occurring at an unprecedented pace. We find it
2 natural to talk about revolutions in genetics,
3 information technology, nanoscale science,
4 engineering, the knowledge base has simply exploded.
5 In a matter of a year, we now know more about us
6 genetically in terms of our sequence than we've ever
7 known in history. The pace of science and technology
8 has accelerated. Although I find it astonishing,
9 it's true, 50 percent of all scientists that have
10 ever lived are living today. Kind of hard to think
11 that as being true, but it is.
12 There is simply more research underway
13 today than ever before in history. The sheer volume
14 of our activities as scientists is putting a strain
15 on our current systems for ensuring adequate human
16 research protection. There are other changes that
17 are increasing the strain. Research is becoming more
18 collaborative, multidisciplinary, in fact it's almost
19 mandatory that you involve many disciplines,
20 especially in health research.
21 And we bring together researchers from
22 many institutions and discipline. There are cross
568
1 sectors. For example, in Bangladesh we have cultural
2 differences that we have to respect.
3 We now have virtual research teams and
4 partnerships that span academia, industry, local
5 governments, state governments, provincial
6 governments. And research is increasingly
7 international in scope with different modes and
8 attitudes on different continents towards the kind of
9 research that we do.
10 We have the ability to call in the best
11 talent worldwide and more and more of the phenomena
12 we study are global in character. For example, in
13 our studies in Bangladesh we have been able to
14 correlate the epidemics rather neatly with sea
15 surface temperature and sea surface height. And this
16 gives us a prediction. So we are involved in
17 satellites in several countries, India, Bangladesh,
18 China.
19 It's not surprising then that we face a
20 host of new challenges in protecting the people
21 engaged with us in our research and we've come a long
22 way from the lone principal investigator like Dr.
569
1 Hansen in Norway working on a disease that he studied
2 so carefully. You know, the single investigator with
3 straightforward protocol, homogenous group of
4 subjects. We are more likely now to encounter
5 cultural, linguistic, legal, policy considerations,
6 cultural considerations when we just begin to draft
7 up plan of action for a research program in almost
8 any field of study.
9 At the National Science Foundation this
10 changing research scene is fast becoming the norm
11 rather than the exception. Our mission is to
12 maintain the health and vitality of fundamental
13 research across all the disciplines in science and
14 engineering and in education at all levels.
15 And in that process we support the
16 disciplines in their constant struggle to reach the
17 -- frontier while maintaining their fundamental
18 capability. Although we support much of the
19 fundamental research that underpins advances in
20 medicine, the NSF does not support medical research.
21 We fund everything else except clinical and medical
22 research.
570
1 And that means much of the research we
2 support does not fit the traditional clinical model.
3 In fact, much of the research that we support doesn't
4 involve humans in any way. That's true, for example,
5 of research on sunspots, and formation of black
6 holes, or fundamental mathematics. But to end my
7 description on that note would leave you with a very
8 incomplete perspective on NSF because we do support a
9 wide range of fundamental research that does involve
10 human participants.
11 Now, before I describe that research, let
12 me just put the NSF activities in a larger context.
13 NSF accounts for about 4 percent of federal research
14 and the development that goes with it. But that 4
15 percent supports about 50 percent of the non-medical
16 fundamental research at colleges and universities.
17 So it is very significant.
18 And there are very important areas of
19 fundamental research directed toward understanding
20 human beings in all their complexity. That
21 percentage is even higher because the education,
22 social, behavioral, psychology, sociology studies,
571
1 anthropology, archeology. Every year NSF supports
2 almost 200, 000 people, individuals. That doesn't
3 count the people who see the IMAX films or the kids
4 who watch the Magic School Bus. We are talking about
5 individuals. And these are scientists, engineers,
6 teachers, students. And you can see, we have a very
7 large stake in maintaining high standards and finding
8 effective ways to ensure adequate safeguards as we
9 move our research agenda forward.
10 There is no question but that a top
11 priority for the research community, for society, and
12 above all for the individuals who are involved in our
13 research are these issues you're discussing.
14 Okay. Now, let me give you a sampling of
15 some of the SNF-supported research that does involve
16 human participation. We have a very large portfolio
17 in the economic, social, psychological, behavioral,
18 and cognitive sciences. The ways we go about
19 studying humans range framework MIIs -- to careful
20 observation of infants to simple anonymous surveys,
21 full range. Many of the questions these
22 investigations address are fundamental to our future
572
1 prosperity and quality of life in this nation. Among
2 them are studies of how infants and children learn,
3 how individuals like us make decisions, how we assess
4 risks.
5 Other research is unravelling the
6 processes that support innovation, creativity, our
7 capacity to adapt to change. In fact, we'll be
8 launching a major study on change and its effect
9 socially, behaviorally.
10 In brief, these studies aim to understand
11 humans, us, in all of our complexity and diversity.
12 Now, so too does the research in groups, communities
13 and populations. Understanding how we organize
14 ourselves, how we behave in groups, how we misbehave
15 in groups, too, I might add.
16 [Laughter.]
17 DR. COLWELL: How we build institutions
18 and how we respond to those institutions and how
19 cultures and societies come into being and how they
20 evolve. These questions cover an entire spectrum of
21 very, very important human activity from industry to
22 politics to culture to law.
573
1 There is such rich territory to be
2 explored here that it brings to mind one of my
3 favorite quotes. It's from the 18th Century poet,
4 Alexander Pope. "The proper study of mankind is
5 man." Except today I'd say, "humankind."
6 Well, I could go on. There are many, many
7 examples, but I wanted to end my comments with two
8 examples that might be less familiar to you. And
9 each in its own illustrates how people entering into
10 our research in new ways and how seriously NSF takes
11 the issue of protecting their interests.
12 Now, the first is from information
13 technology and the networking that's associated with
14 IT. Few of us welcome have predicted the speed with
15 which these technologies have become pervasive
16 influences in our lives. Just think about it, bar
17 codes in the supermarkets which we all take for
18 granted, nearly a decade ago we were fighting about
19 whether we really wanted that infringement on our
20 privacy. Well, here it is.
21 There's no doubt that we need to
22 understand the human and social dimensions of these
574
1 changes. And so NSF is sponsoring research on the
2 effects of IT in the Internet on human learning and
3 other aspects of human psychology. And we're
4 supporting research on the human computer interface
5 with these wide-ranging potentials to provide
6 universal access, including the development of new
7 communication resource for people with disabilities.
8 If some of the things that we have underway come to
9 fruition, we will quite possibly see Christopher
10 Reeve walk. It's not out of the question. So the
11 shunts for the brain to pass the lesion in the spinal
12 cord.
13 These studies involve a reciprocal
14 relationship between humans and technology. Computer
15 scientists learn from the cognitive sciences,
16 linguistics, neurobiology and vice versa. They learn
17 from the IT as well. These technologies are rooted
18 in math, physics, engineering, computer science. But
19 the research agenda is increasingly turning toward
20 humans.
21 In the future as the pace of technological
22 change accelerates, we're going to see these studies
575
1 integrated into research programs from the very
2 beginning. We will need innovative and very flexible
3 models that allow us to address the new developments
4 in the context of human research protections.
5 Now, the common rule, familiar touchstone,
6 has always provided us with the flexibility to allow
7 us to accommodate the dramatic changes that have
8 swept through science and engineering. But it has
9 also kept us attentive to the interests of research
10 participants. So it's important as we consider the
11 need for change and the approach that we take to very
12 high-risk studies, that we maintain the flexibility
13 for research that is not high-risk. Flexibility for
14 research that is not high-risk.
15 Now, I suspect that in your discussions
16 yesterday with Francis Collins when you talked with
17 him, that we're a step in this direction. In a
18 similar vein at NSF we're beginning to anticipate the
19 impacts of nanotechnology and the ethics of its use.
20 It's really astounding some of the things that will
21 be happening with motors that are the size of maybe
22 two or three or four red blood cells stacked one on
576
1 top of another. It's really, really amazing. We
2 recently held a workshop to discuss these issues.
3 So let me conclude with another example
4 that takes us even further away from the traditional
5 models of work with human participants. In some
6 cases we need to map new terrain, not only in
7 designing our research, but also in establishing
8 nurturing relationships and collaborations with those
9 with whom we wish to study. Now, what's the example?
10 All of the NSF-supported research in the
11 Arctic adheres to broad guidelines. It's agreed
12 through interagency process, in fact, I go from here
13 to the Arctic Commission on which I serve. Now these
14 guidelines establish the ethical responsibilities of
15 researchers toward the people of the north, their
16 cultures, their environment. The guidelines are
17 called the principals for the conduct of research in
18 the Arctic. They're intended to promote neutral
19 respect and communication between the scientists and
20 the northern residents. In one of the NSF's arctic
21 projects, a team of UPIC elders traveled to a museum
22 in Berlin to work with the astonishing, undocumented
577
1 collection of UPIC cultural artifacts. They were
2 brought from Alaska to German in the late 1880s.
3 Three of the elders spoke only UPIC. Two
4 were in their 80s and the other others were in their
5 70s. They worked with over 6,000 objects describing
6 their significance, their use, their providence. And
7 we captured their research in photographs and on
8 videotape.
9 Now, Ann Feenin Reedin [ph], the cultural
10 anthropologist, who worked with the elders called
11 this field work turned on its head. Because the NSF
12 grant didn't fund her work but went directly to the
13 Association of Village Council Presidents in Alaska.
14 And the group of UPIC leaders identified their own
15 research objectives and they chose their own
16 researchers, their elders to conduct the study.
17 The elders were at once, at the same time,
18 the researchers and the subject of research. In this
19 case they weren't even interested in the return of
20 the artifacts which you might suspect would be the
21 end of a story. Instead, they just wanted to
22 document and preserve the aspects of their culture to
578
1 enlighten and empower their descendants. A perfectly
2 human desire. And the research was immeasurably
3 enriched by their participation at every stage of
4 this research project.
5 I know we can learn from these examples.
6 They teach us that embracing our unsung heros and
7 respecting their interests is the only way to
8 approach our research. And so with these thoughts
9 that I've shared with you, I'm grateful to have had a
10 chance to talk with you. Thank you.
11 [Applause.]
12 CHAIRPERSON MARSHALL: Rita, thank you
13 very much -- Dr. Colwell. You've enriched our
14 thinking. I was looking at the faces of the
15 committee members and our liaisons and the public
16 members as you were speaking and I think they were
17 just rapt with attention to the stories that you were
18 telling.
19 Let me ask whether anyone has questions of
20 Dr. Colwell. I would like to say to you, Dr.
21 Colwell, that we, as a committee, enjoy the fruitful
22 interaction with Phil Rubin and with Jack Mitchell
579
1 who are ad hoc -- or liaisons with the NIH. We
2 certainly had some -- in the last two days, I think,
3 some good conversations back and forth. And we also
4 want you to know that we as a committee are here to
5 serve you in any way that we can and certainly as new
6 research paradigms evolve, we would like to be a part
7 of that and to help inform the research ethics of
8 those new paradigms. So we are at your service, we
9 would like for you to know that.
10 Let me open the floor and ask whether any
11 of our committee members and our ex officio members
12 or our public members would have questions of Dr.
13 Colwell. Adil.
14 DR. SHAMOO: [Off mic.] Dr. Colwell --
15 colleague of your at the University of Maryland,
16 School of Medicine. We have met a few times.
17 DR. COLWELL: Yes.
18 DR. SHAMOO: My question to you is, as you
19 know, the human -- protection of responsible conduct
20 research and by the time we train scientists in other
21 requirements for responsible conduct in human
22 research it's really too late. they get that -- they
580
1 should get that training in high school, even middle
2 school, and certainly in college. NSF plays a major
3 role in educating especially in college campuses all
4 across the country. How can NSF help us by preparing
5 some of that preliminary training in responsible --
6 research inculcated in those --
7 DR. COLWELL: Again, there are many ways.
8 We do have a group at NSF, Phil Rubin's group -- by
9 the way, I brag about NSF. It's an extraordinary
10 agency with extraordinary people and you've met a
11 couple of them.
12 Rachelle Hollander is someone who is
13 highly respected, one of our NSF people and her group
14 is involved in funding research. And we have an
15 education and human resources directorate with
16 educating K-12. In fact, the president has in the
17 current budget designated the NSF as the lead agency
18 for science and math education which we take very
19 seriously and very responsibly and welcome.
20 A president of the Sigma Xi some years
21 ago, we produced a booklet, ethical conduct in
22 research and we distributed that very, very widely.
581
1 That has been very useful because it has been
2 included in curricula. The Academy -- the National
3 Academy of Sciences has also produced documents, and
4 I'm sure you know all of this. But I think it's very
5 important to make these documents available to
6 provide them to schools and to include them in
7 science teaching. So I think you have a very valid
8 point.
9 In fact, we really ought to include them
10 in some ways in the first four years, because we have
11 discovered that that's when kids are really
12 scientists and then that valley of death between
13 grades 4 and 8 which we've got to work on to keep
14 them as scientists. So a very early education is
15 important.
16 CHAIRPERSON MARSHALL: Others who might
17 have questions or comments that they would like to
18 make? Yes, Elliot.
19 DR. DORFF: In our December meeting Felice
20 actually made a report about -- based upon the study
21 of the American or the documented American
22 Association of University Professors about how the
582
1 common rule did and did not apply well to non-
2 scientific research using human subject. I mean,
3 that is non-medical research. Right.
4 [Laughter.]
5 DR. DORFF: Yes, that's right. That's
6 right. I'm sorry. That's a very bad error. Right.
7
8 [Laughter.]
9 DR. DORFF: I'm sorry. I'm a philosopher,
10 what do you want?
11 [Laughter.]
12 DR. DORFF: But I was wondering, to what
13 extent does NSF have varying rules about human
14 subjects, you know, protection of human subjects
15 given the various -- I mean, because you're talking
16 about things from -- medical things like cholera to
17 anthropological research in Alaska, to -- I mean,
18 clearly, as you said, you're from one end of the
19 spectrum to the other, from a questionnaire to an
20 MRI.
21 DR. COLWELL: Right. We don't really have
22 varying rules. In fact, I'd turn to Phil because
583
1 it's my understanding that it's pretty much across
2 the board.
3 DR. RUBIN: [Off mic.] It's pretty much
4 across the board the policy usually the guidelines
5 that they set down -- not signatories -- Subpart D --
6 there are a couple of -- that I could go over in
7 detail, but in general we follow the guidelines here,
8 while we're here and while we're working with this
9 group -- in my IRB chair --
10 The point of the enterprise is to work
11 with this group on one other thing and follow up on
12 an earlier question in training and in new programs
13 -- [Off mic.] built into --
14 AUDIENCE PARTICIPANT: Use the microphone
15 so we can record you.
16 DR. RUBIN: We basically go by the
17 standard guidelines that we would do under NIH grants
18 with the exception that we try to emphasize that for
19 many of our enterprises, not all, where things are
20 low risk. And in some of the research, like usually
21 human computer interface, interface psychology
22 experiment, you're seeing words on the screen and
584
1 hitting a button. We want to make sure that the
2 valuable resources that are needed to protect
3 subjects are put on the high risk enterprises.
4 CHAIRPERSON MARSHALL: I think I've got
5 Bob and then Abbey.
6 DR. COLWELL: And then I have to bolt.
7 DR. R. LEVINE: I enjoyed your
8 presentation very much. I'm a member of one of your
9 working groups, the one that's directed by Stuart
10 Platner, and he's trying to find out or having us
11 explore together how particularly social and
12 behavioral scientists can find their way in the
13 current complicated regulatory ecology. I think also
14 that there are some guidelines out there that if
15 interpreted strictly and applied to your work could
16 -- I think during your very interesting story of your
17 work with Cholera I was reflecting on the fact that
18 it's a violation of the Declaration of Helsinki and
19 maybe you would want -- well, I mean, the Declaration
20 of Helsinki is something that we've discussed here.
21 It rules out research in a lot of important and
22 interesting areas and one of them just happens to be
585
1 yours.
2 DR. COLWELL: Well, you mean cholera or
3 Bangladesh?
4 DR. R. LEVINE: No, I'm talking about the
5 use of simple preventions that one can afford in
6 Bangladesh without using what might be called the
7 best proven therapeutic method as it exists in other
8 parts of the world.
9 DR. COLWELL: This area is a clinical
10 research area. So, we, the villagers are monitored
11 by physicians on almost a daily basis. And this is
12 under NIH guidelines and it's NIH supported. So it's
13 not a rogue study.
14 [Laughter.]
15 DR. R. LEVINE: The point I'm really
16 trying to make indirectly is that yours is not a
17 rogue study like many, many research projects it's
18 funded by the National Institutes of Health.
19 DR. COLWELL: And I should have the
20 National Institutes of Nursing because they are the
21 ones --
22 DR. R. LEVINE: Well, they're one of the
586
1 "i"s at NIH.
2 DR. COLWELL: That's okay, they don't
3 always get the credit they really deserve. Right?
4 DR. R. LEVINE: But like so many ethical
5 and scientifically valuable studies funded by all of
6 the "i"s at NIH, they are in violation of the
7 Declaration of Helsinki and it's not because they're
8 doing anything unethical, it's because the
9 Declaration of Helsinki is wrong.
10 [Laughter.]
11 DR. COLWELL: I've been asked to do a lot
12 of things, but to change the Declaration of Helsinki
13 single-handedly --
14 PARTICIPANT: We're doing that.
15 CHAIRPERSON MARSHALL: Abbey, you have
16 question?
17 MS. MEYERS: Well, I want to ask you about
18 the third-world countries. We have this intricate
19 set up of IRBs and all these safeguards here, but one
20 of the incidents that triggered this whole
21 investigation of ethics is the HIV study with
22 pregnant women in Africa. Now, what are we to do
587
1 about third-world countries that don't have patient
2 protection systems?
3 DR. COLWELL: Well, fortunately, I've done
4 my work in Bangladesh where we in fact have
5 superimposed the systems employed here. They do have
6 the subject review committee at the International
7 Center for Diuril Diseases Research Bangladesh where
8 I have worked for the last 25 years. They have the
9 same kind of committees. In fact, the director,
10 David Sach is a Johns Hopkins physician detailed to
11 ICDRB.
12 I've done some work in Africa and all I
13 can say is an off-the-top-of-the-head response which
14 is that you follow the rules wherever you are and you
15 simply impose them as you do your work.
16 MS. MEYERS: You followed the rules in --
17 DR. COLWELL: In whatever I must do for my
18 students and my subjects and my research here in the
19 United States is what I feel I must do when I'm in
20 Africa or in Bangladesh or in Pakistan.
21 MS. MEYERS: So you're following American
22 rules?
588
1 DR. COLWELL: Yes.
2 DR. R. LEVINE: Abbey, I'm afraid you
3 believe too much of what you're reading in the
4 papers. The places where the short duration AZT
5 trials were done in developing countries had what
6 they called "Research Ethics Committees" which are we
7 called institution review boards.
8 CHAIRPERSON MARSHALL: Thank you so much,
9 Dr. Colwell.
10 [Applause.]
11 CHAIRPERSON MARSHALL: We are going to
12 proceed with the children's discussion for the next
13 half an hour. So, Alan Fleischman, Dr. Fleischman is
14 going to retake whatever control one can have over
15 this motley group here and in the room.
16 [Laughter.]
17 CHAIRPERSON MARSHALL: The out-of-control
18 group.
19 DR. FLEISCHMAN: I actually was enjoying
20 this.
21 [Laughter.]
22 DR. FLEISCHMAN: I was quite taken by the
589
1 Arctic adventure.
2 I would like to talk about the fourth
3 issue that the working group thought was the most
4 perhaps controversial and then do some summation all
5 in this 30 minutes. And the fourth issue speaks to
6 part of the answer to question six, the expectations
7 of child research participants and their parent or
8 guardian for the direct benefits of the child's
9 research involvement.
10 And here the working group focused
11 primarily on the issues of Phase I trials and the
12 concerns about therapeutic misconceptions, issues
13 that have been well written about and of concern.
14 The group started with an acceptance of
15 the critical importance of Phase I trials for
16 children. That is to say, if you could not do
17 research in Phase I trials for children, then you
18 could never discover new therapeutic interventions
19 for children. And that, in and of itself was felt to
20 be problematic.
21 So the question was, how have we done
22 Phase I trials, and how ought we to do Phase I trials
590
1 in terms of justifications?
2 The working group was also aware that some
3 groups have attempted to do what are called Phase I
4 and II trials. That is to say looking at both
5 toxicity and efficacy at the same time in creatively
6 designed trials, or at attempts at creatively
7 designing trials.
8 In an attempt then to generate some
9 potential of therapeutic benefit in the trial. So
10 here again, I ll explain to you the workgroup's
11 conclusions or recommendations, but we are in need of
12 some conversation and some assistance in thinking
13 this issue through. The workgroup believes that the
14 issue of therapeutic misconception research is very
15 troubling and most troubling perhaps in Phase I
16 trials, yet an important area for children s
17 research.
18 Phase I trials generally have a very low
19 likelihood of or no potential for benefit and that is
20 even controversial. If we speak to some of our
21 families, particularly advocates in the area of
22 cancer treatments, the families have told us that
591
1 there is the hope that the next new drug will be the
2 right drug. That even being in the Phase I trial
3 might show miraculously, and I use their language,
4 that there is some biologic or perhaps therapeutic
5 benefit and then that drug could be used for their
6 child in that therapy.
7 Even though they are aware and
8 knowledgeable about what the purposes of the research
9 is and that is for toxicity measurement, they argue
10 that these are far more symbolic for them than what
11 they are in terms of the classic pharmacological
12 approaches. And I think that I've personally and I
13 think the workgroup as well is concerned about
14 understanding that perspective and giving it some
15 value in this whole conversation. The perspective of
16 the families of children with life-threatening
17 diseases.
18 Therefore, the workgroup concluded that
19 such trials ought to be allowed, that it was
20 extremely important for new therapies to be
21 introduced, but the potential subjects for such
22 research need to be sick children, need to be
592
1 children for whom standard treatments have failed to
2 offer the hope of cure, and I personally dislike and
3 won't use the language of "the children have failed."
4 It's the rest of us that have failed.
5 And the alternative options include
6 palliative care, noninterventions which need to be
7 both offered and perhaps integrated into these
8 trials. But that IRBs ought to be allowed to approve
9 such studies and we need to consider whether they
10 ought to be approved through the mechanisms of 406 or
11 407. And these I think to justify these studies will
12 take some hard thinking and in it's important that we
13 consider this.
14 From the parents' perspective they see
15 this as potentially benefiting their children. From
16 the academic's perspective they see that as hopefully
17 a minor increment over minimal risk research with
18 safeguards to assure the children's safety.
19 And then finally we talked a little bit
20 about Pharmacokinetic Phase I trials or the first
21 steps of understanding the treatments for children.
22 Those I think are different kinds of trials because
593
1 they actually have already had a substantial amount
2 of work done in adults and others for whom we really
3 do know something about toxicity and have some
4 ability to think about that and can do efficacy
5 studies at a much earlier phase. So that wasn't as
6 troubling in this regard.
7 So let me open up this conversation, I
8 don't know if I have articulated this well. But let
9 me open up this conversation and turn to Bob for his
10 wisdom.
11 DR. R. LEVINE: Alan, that s a very good
12 presentation. I want to bring up a point that didn t
13 become clear until toward the end. That, if I hear
14 you correctly almost everything you said until the
15 last minute was addressed to Phase I trials in the
16 field of oncology, cancer chemotherapy.
17 DR. FLEISCHMAN: And other life-
18 threatening kinds of diseases.
19 DR. R. LEVINE: Well, in general Phase I
20 studies on other types of life-threatening diseases
21 with the exception of most infections are done in
22 normal controls and that presents us with a very
594
1 important problem but a different problem.
2 The problem with Phase I oncology, I don't
3 know if everyone here appreciates what Phase I
4 oncology looks like. Do you all know about a dose
5 escalation design?
6 DR. FLEISCHMAN: Why don't you go ahead
7 and unpack that.
8 DR. R. LEVINE: All right. What you do is
9 you start the subjects and they're usually as, Alan
10 pointed out, people who have cancer and where all
11 known therapies have failed to produce any good
12 effect or they may have produced a good effect and
13 now the tumor has become resistant. You start people
14 out then on a cancer chemotherapeutic agent that has
15 never been tried before in humans, or if it has been
16 in the case of children, sometimes -- most of the
17 time they've been tried first in adults.
18 There is a dose escalation design. You
19 begin with a low does that you do not expect to have
20 much bad effect and you do not expect it to have any
21 good effect. And then you keep elevating this dose
22 until you get to a level where two out of three
595
1 subjects have life threatening complications. Then
2 you drop back one dose and say that is the maximum
3 tolerated dose and it is the maximum tolerated dose,
4 the MTD that is then used in your Phase II studies
5 where you're beginning to look for therapeutic
6 effect.
7 These studies are highly problematic with
8 adults. We tell -- well some data. In 1,200 and
9 some odd consecutive Phase I oncology studies carried
10 out at National Cancer Institute, only 2 percent of
11 the patients had even a partial remission and .16
12 percent had a complete remission.
13 The first time I presented those data in
14 public I got a letter from the woman who claimed to
15 be the .16 percent. She had far advanced breast
16 cancer, volunteered to get in the study and had a
17 complete remission and years later there were still
18 no evidence of disease. And she had changed her
19 career form teaching anatomy to teaching medical
20 ethics. Possibly an adverse effect.
21 [Laughter.]
22 DR. R. LEVINE: The problem we have is
596
1 that we will present these data to adults who are
2 candidates for a Phase I oncology studies. We say
3 there is very nearly no possibility of benefit and
4 depending upon where you are in the dose escalation
5 there could be very grave adverse effects. They
6 agreed to participate and the next day you walk onto
7 the oncology unit and say why are you in the study
8 and they say it's the only chance I have.
9 Now, with children the benefit side of
10 the equation is somewhat better. In Phase I they
11 have had a higher percentage of partial and complete
12 remissions. But it is still not a very good balance
13 and the problem of getting consent to this or
14 permission plus assent I think is probably even more
15 vexatious than the problem with adults. Thanks.
16 DR. FLEISCHMAN: Yes, Denyse.
17 DR. THORNLEY-BROWN: I'm a little hung up
18 by the term "cure" in here, because there are a lot
19 of treatments that may not cure people but can
20 improve their quality of life and to offer parents
21 something -- a Phase I trial that probably won't cure
22 or may not even palliate, as opposed to something
597
1 that may be beneficial to the child. That word just
2 kind of bothers me. I think that something needs to
3 be added. So if standard treatments have failed to
4 offer the hope of cure or improvement of quality of
5 life, or something like that. Because I think that
6 one word is bothersome.
7 DR. FLEISCHMAN: Thank you. Adil.
8 DR. SHAMOO: Thanks. I have a couple of
9 quick questions for clarification from you. Is the
10 Phase I trials you are discussing, is that 407?
11 Under 407 or not?
12 DR. FLEISCHMAN: The working group thinks
13 that they would not be under 407.
14 DR. SHAMOO: So they would be under 406?
15 DR. FLEISCHMAN: Well, that s where we re
16 looking for conversation of whether they re under 406
17 or 405.
18 DR. SHAMOO: Well, because that s a --
19 yeah, that s a very crucial what we do about it.
20 The next question is, the way you said
21 that orally versus what s written. Orally you said
22 basically, it s, my understanding it s prohibited on
598
1 healthy children, Phase I clinical trials on healthy
2 children. They have to be sick. Is that what you
3 said?
4 DR. FLEISCHMAN: What I m specifically
5 talking about are Phase I trails in this paragraph on
6 oncology drugs with seriously ill children who s
7 future looks grim and for whom the treatments have
8 not resulted in enhancing the quantity or quality of
9 their lives. Or as Bob pointed out, they were better
10 and have now gone into remission.
11 DR. SHAMOO: My question is then the same
12 one a few hours ago and that is, when are we going to
13 talk about introducing new drugs on healthy children
14 that are not sick? This is what Abbey s question is,
15 this is what my question is. Are we going to talk
16 about it or are you just saying that will never
17 happen? That according to 407, that is prohibited
18 only the Secretary after public hearing can approve
19 it. Are we still stuck with that?
20 DR. KOSKI: I can think of very few, if
21 any, examples where the first use of any new
22 pharmacological agent is in children, certainly in
599
1 healthy children. Every new pharmaceutical agent
2 that I m aware of apart from, maybe we can come up
3 with some kind of an unusual example that is a
4 disease that s unique to a child, that s the only we
5 that you could ever introduce it and there are
6 probable some examples that we could search out, I
7 would bet.
8 To my knowledge just about every new
9 pharmacological agent is first introduced for Phase I
10 testing in adults and generally the oncology drugs,
11 those which have severe toxicity are generally in the
12 people who are ill, whereas other drugs would be
13 tested in normal healthy volunteers.
14 DR. SHAMOO: But my concern is that we
15 define for the purpose of allowance of research on
16 healthy children, we define the benefit in such broad
17 terms that was the 407 FDA advisory, to include
18 futuristic disease.
19 So somewhere there is the thinking and I
20 just want to confirm it then. Somewhere there s the
21 thinking that we are going to use those new drugs on
22 healthy children. If that is the consensus that we
600
1 will not use healthy children to introduce new drugs,
2 we want to have it on the table and we all agree,
3 that that practice which you said are extremely rare
4 is not as rare as you re saying, but if that is the
5 consensus then it s wonderful. But that s not my
6 understanding from written documents that I have
7 read.
8 DR. FLEISCHMAN: The working group would
9 be happy to review any specific examples that could
10 clarify your concern for us. Because like Dr. Koski,
11 we don t -- we can t think of a circumstance. If
12 there were new drugs for child-specific diseases then
13 they would be studied in the children with those
14 diseases and they might well be studied in such
15 children.
16 DR. SHAMOO: Fenfluramine study was not
17 sick children. They were healthy children and was
18 approved under not for 407, but for 406.
19 DR. R. LEVINE: I must say that
20 fenfluramine was a single dose and it was not a Phase
21 I study. It was a dose that was designed to study
22 the basic biology and to this day no one has ever
601
1 attributed any toxicity to a single dose of
2 fenfluramine.
3 DR. SHAMOO: But it was on healthy
4 children that are not sick.
5 DR. R. LEVINE: No one is disputing that.
6 It's just that does not happen to be the topic we re
7 discussing right now.
8 DR. FLEISCHMAN: Dr. Koski and then I d
9 like to weigh in on this.
10 DR. KOSKI: You know, if we put on the
11 futuristic hat that you're suggesting, Adil, one
12 could for instance in the advances of medicine
13 identify a possibility where there is a genetic
14 modification factor that might be utilized to
15 actually correct a developmental abnormality that
16 could result in a deformity or some other kind of
17 thing at birth that could actually be delivered
18 perhaps in to a fetus or something. I m really going
19 off the wall here.
20 But where the only way that one could test
21 it, the only applicable scenario would be in a child
22 for the Phase I study. There s no way that you could
602
1 really tell, I mean you could squirt it in I suppose
2 an adult I suppose to see whether or not it would
3 make them sick. Even there it s hard to come up
4 where we would actually end up in a situation of
5 doing the first testing in healthy children --
6 DR. SHAMOO: Then why don t we have
7 language which is very clear such that the
8 fenfluramine type of experiment, even though it s one
9 dosage, fenfluramine is a high-risk drug, was used on
10 healthy children, that that will not happen again.
11 Otherwise, what we are doing, we are
12 having again not clear language for IRB s to make 407
13 type of protocols, speak up Abbey with me -- 407
14 protocols as 406 and they are then allowed. Why
15 aren t we so clear then?
16 I m agreeing with Greg and I m agreeing --
17 I love you both for saying that, but lets but it in
18 the language, in English, black and white. Not in
19 Arabic in my native language.
20
21 DR. FLEISCHMAN: Let me keep us on track
22 here though. Because we began this conversation
603
1 discussing Phase I trials. Whether you and I agree
2 that the fenfluramine study ought not have been
3 approved, has nothing to do with the conversation
4 about Phase I trials.
5 DR. SHAMOO: [Off mic.]
6 DR. FLEISCHMAN: Well, no it doesn t. We
7 could in fact talk about that study as an example of
8 whether we, if we were the IRB reviewing it, would
9 have allowed it to happen. And we could discuss that
10 case example and we might come to agreement or we
11 might not. But it was not --
12 DR. SHAMOO: But you said 407 versus 406.
13 You said this is part of our discussion. The Phase I
14 clinical trial, you said, and we want to decide
15 whether it falls under 407 or 405, even you said, not
16 406.
17 DR. FLEISCHMAN: Let me see if I can
18 recap for a moment so that we re clear. Okay.
19 Because I don't mind the direction you're going. I
20 just want to be sure that when we get there we know
21 where we've been and where we're going.
22 The issue around whether normal volunteer
604
1 children, if we can use that term -- in normal
2 healthy children who assent and are given permission
3 by their parents to be part of a study that has
4 something to do with the medication placed into them
5 in order to study some physiologic phenomenon, that
6 is not a Phase I trial. That is a research study.
7 It's got a hypothesis, it's got a question. It needs
8 to be assessed as to what is the level of risk of
9 putting a chemical into a youngster.
10 We have to decide, as an IRB, if we were
11 looking at it, is there any potential that that
12 intervention can give benefit? We have to decide,
13 does that child fit into a child with a disorder or
14 condition that's relevant for the study, and then we
15 figure out whether it fits in 405 or 406 and if it
16 doesn't, but we as an IRB think it's an absolutely
17 important study that we as an IRB think ought to
18 happen, but we can't approve it, then we kick it up
19 to a 407 review as per the recommendations of the 407
20 committee.
21 DR. SHAMOO: You are saying we will not
22 weigh in, in such kind of an issue. We as a
605
1 committee, as NHRPAC, we will not make a statement on
2 healthy children having new drug, high-risk drug
3 introduced into them?
4 Because what I understood you and Abbey
5 understood you, and I asked that specific question to
6 you, Alan, you are really doing a good job on both of
7 us it looks like and maybe not intentionally. When I
8 asked about when is the time that we're going to talk
9 about introducing new chemical entities or new drugs,
10 need not be a drug, new chemical entity and new drug
11 into healthy children is that we have to wait for
12 Phase I trial or I could bring it up when we were
13 discussing 407. And you said, no, let's wait for
14 Phase I.
15 Now, that I bring it here, this is not a
16 topic of conversation. My thinking is that we need
17 to weigh in, make it very clear through our
18 conversation and whatever we agreed on, what we are
19 going to do when we introduce, and I give you, you
20 said there is no example. I brought you an example,
21 then that's not the right example.
22 Fenfluramine, a high-risk chemical entity,
606
1 is not even a drug, was tested on healthy normal
2 children, all blacks and Hispanics, in New York City
3 for over 100 children. They were paid 25 buck to go
4 to Toys-R-Us -- a $125 to the parents plus other
5 amenities. Now I want to know if that kind of
6 research will continue under our own workgroup
7 recommendation? Is that clear.
8 DR. FLEISCHMAN: I think that we could
9 analyze that specific case here. I don't think we
10 would need to either write new regulations nor even
11 interpret present regulations to come to conclusions
12 concerning that specific protocol.
13 DR. SHAMOO: I will then ask the committee
14 and ask Mary Faith Marshall that we discuss that kind
15 of an issue either as a committee as a whole. It's
16 your committee, you are the chair, you are refusing
17 to even consider its deliberation. We should
18 continue on that and we will drop the discussion.
19 Because my understanding and Abbey's understanding,
20 and she doesn't have a foreign accent, was that we
21 will discuss it.
22 DR. FLEISCHMAN: Don't get me wrong, Adil,
607
1 and you don't -- and you and I actually don't agree
2 on -- don't disagree on this issue. The workgroup
3 would be happy to discuss that issue. The workgroup
4 would be happy to come out with a comment for you on
5 that issue. I don't think that's a problem. I'm
6 just trying to help us to understand that in the
7 frame of reference of where we are the workgroup felt
8 no need to make a comment about that.
9 DR. SHAMOO: There is a great need.
10 DR. FLEISCHMAN: Right. So the workgroup
11 would be happy to take that under consideration and
12 evaluate it and come back to the committee with some
13 comments about it. I don't think that's a problem
14 for either me or the workgroup.
15 DR. KOSKI: I think the important point
16 here, Adil -- I mean, your point is a good one, but
17 in the context of the discussion that we're having,
18 what you're talking about is not a Phase I trial.
19 And that's the difference.
20 DR. SHAMOO: [Off mic.] I asked that
21 question three hours ago.
22 DR. KOSKI: I understand.
608
1 DR. SHAMOO: [Off mic.]
2 DR. FLEISCHMAN: I will take
3 responsibility for having misunderstood the substance
4 of what you were asking then, which I thought --
5 DR. SHAMOO: [Off mic.]
6 DR. FLEISCHMAN: -- was part of the Phase
7 I trial because of the language you used at the time.
8 Now, again, there's a conflation here. We are not
9 talking about a Phase I trial, so we need to have a
10 conversation about it in a separate conversation.
11 CHAIRPERSON MARSHALL: We've talked about
12 the use of particular cases or example to help us and
13 to help others interpret what we're trying to say and
14 we have a list at the end of our draft comments.
15 So, Adil, I understand and I hear what
16 you're saying, that you have a need to have this
17 particular issue of new drug high-risk in healthy
18 children explicated with the use of an example. We
19 will do that.
20 DR. SHAMOO: Thank you.
21 CHAIRPERSON MARSHALL: And we will also
22 ask for your involvement in terms of that specific
609
1 example and how it's explicated, both you and Abbey.
2 DR. FLEISCHMAN: Let me be even more clear
3 though, Mary Faith. We are not talking about a new
4 drug being introduced into children, Adil. What we
5 are talking about is a provocative agent to study
6 some kind of physiologic response. And we may agree
7 that we shouldn't do that in some circumstances;
8 maybe all circumstances. But in some circumstances,
9 certainly. But it's not the same thing as taking a
10 drug, meaning something that we hope has some
11 therapeutic value and studying it to see if it has
12 therapeutic value.
13 What that specific research study was
14 about was a physiologic provocation by a chemical in
15 order to understand something about physiology and
16 prediction.
17 Now, you and I may agree that we shouldn't
18 do that. I'm only trying to get us to understand the
19 distinction between taking a chemical agent that we
20 think has therapeutic intervention potential versus
21 understanding physiology.
22 DR. SHAMOO: No, I think -- Abbey, go
610
1 ahead.
2 DR. FLEISCHMAN: Abbey?
3 MS. MEYERS: Okay. You know, a lot of the
4 research that is going on is privately funded. So a
5 lot of the information doesn't come out to the public
6 unless the New York Times or the Enquirer gets ahold
7 of it.
8 Now, let's look at a drug that was
9 specifically developed for children, the lung
10 surfactant. I think there's three or four of them on
11 the market. I think Galaxo makes one of them. They
12 were all studied on children. They all had to start
13 in the Phase I trial. Was it studied just on
14 children with respiratory distress syndrome, or was
15 it given to healthy infants along with the --
16 DR. FLEISCHMAN: Abbey, I was there.
17 That's what I did for a living in my prior life as
18 the director of neonatology for a very large program.
19 There were no normal children given surfactant down
20 their airways.
21 The studies were done after very
22 significant research in animals, some of the first of
611
1 it done actually when I was a fellow at the NIH in
2 1971 in which we used both monkeys and sheep. It was
3 then escalated to humans after a tremendous amount of
4 work in animals and animal models. And it was never
5 given to healthy children. I don't think it has ever
6 been given to healthy children. But it was given to
7 very critically ill, sick, premature infants with
8 full and informed consent and it became a very
9 successful therapeutic intervention which has
10 dramatically impacted on the survival of premature
11 infants.
12 But, there was never a request for it to
13 be given to healthy children. There was never, to my
14 knowledge, from any drug company or anybody else.
15 There was never, to my knowledge, again, physicians
16 who were interested in doing that, in healthy
17 children.
18 MS. MEYERS: Were you involved in the
19 development of lung surfactant, the four or five
20 brands that are out there so that you could
21 definitely say it was only given to sick children?
22 Do you know?
612
1 DR. FLEISCHMAN: Well, no, I don't. But I
2 was, for years, at every meeting at which surfactant
3 was talked about. I mean, these were commercial as
4 well as academic ventures. I just -- it would be --
5 I could not believe that that happened. I honestly
6 can't. I can't conceive it. And I can conceive a
7 very cynically bad things.
8 [Laughter.]
9 DR. FLEISCHMAN: But I just can't -- this
10 is my friend.
11 MS. MEYERS: What we're saying is that
12 somewhere the federal government should prohibit a
13 drug like that being developed for sick children from
14 being given to healthy people. That's all we're
15 asking.
16 DR. FLEISCHMAN: What I'm saying is, I
17 think it does. You see, that's why I don't have a
18 problem with this. I don't think there's anybody in
19 the pharmaceutical industry or in the academic
20 pediatric or non-academic pediatric community that
21 believes it's not illegal to do that.
22 DR. SHAMOO: Why don't we then make such a
613
1 statement, Alan? If we suspect that's happening --
2 it has happened. You see, you are teasing out my
3 chemical entity as a provocative agent versus drug.
4 I don't like that. My chemical entity includes drugs
5 in it. I wanted that prohibition in healthy children
6 whether it is a chemical entity fenfluramine or a new
7 drug. Otherwise you are leaving the door open that
8 drugs can be used for the first time on healthy
9 normal children. Because you say it and I don't want
10 your oral words, just what we are recording here as
11 the gospel and as a regulation.
12 DR. FLEISCHMAN: Judy and then Susan.
13 DR. SIEGEL: I actually think, Adil, there
14 are two discussions here. One is drug development of
15 potential therapeutics. When you use the word "Phase
16 I" you are talking about a phased development of a
17 drug.
18 DR. SHAMOO: [Off mic.]
19 DR. SIEGEL: Versus what you're talking
20 about with fenfluramine, which, I mean, you get it in
21 adults, you get it where you use drugs as challenges,
22 where you use drugs to study disease, but you're not
614
1 studying the drug itself for its potential
2 therapeutics.
3 I think if you look in adult drug
4 development you will also find there are instances in
5 adult drug development that aren't oncology studies
6 where you would never give the drug for the first
7 time to a healthy volunteer because probably that
8 healthy volunteer adult could not tolerate it.
9 Drugs for schizophrenia, healthy
10 volunteers do not tolerate those drugs particularly
11 well, especially in drug doses that could be
12 therapeutic.
13 Why would you give that drug to a person
14 who couldn't tolerate it? I would go the same route.
15 If you're saying that do the regulations prohibit
16 giving a drug with potential major toxicity, to
17 anyone, a child or an adult, who could not or should
18 not tolerate that drug, my sense is that the
19 regulations do cover that versus using a drug as a
20 challenge or a provocative agent for something that's
21 totally out of the drug development, a drug
22 development scenario. And I'm wondering whether
615
1 there aren't maybe differences in those two types of
2 research that we really need to deal with.
3 DR. FLEISCHMAN: I've got on the list,
4 Susan, Margaret and Bob, and then Adil and Elliot.
5 MS. KORNETSKY: The only thing I want to
6 add is I understand what Adil's comments are and sort
7 of what he wants to ask the working group to do. I
8 have problems thinking about this committee making a
9 statement that a certain type of research may or may
10 not be permitted.
11 I think what would be more reasonable, and
12 I can't believe I'm saying this not as -- I'm not a
13 regulator -- is more to take those examples and try
14 to work them through what we have existing in our
15 regulations and to do several examples of that. But
16 to come across with a statement. I hear there was
17 discussion here about a drug, is it an
18 investigational drug, is it an approved drug, is it
19 for therapy, is it for provocative? It's very
20 difficult to come out and just make general broad
21 statements. And I think each sample or each example,
22 and perhaps we can use your example, but to come out
616
1 of that and work through the regulations to see
2 whether it's permissible or not and not to make just
3 broad general statements about it.
4 DR. FLEISCHMAN: Margaret.
5 DR. BORWHAT: Well, I appreciate the
6 distinction you made and the clarification,
7 especially about the study Adil was talking about.
8 But for clarification what is the controlling legal
9 authority for research studies like that? We're
10 talking about very specific regulations here. If
11 these regulations don't cover the type of study he's
12 mentioning, what regulations do?
13 DR. FLEISCHMAN: I think they do cover.
14 You see, that's the point. I mean, the working group
15 didn't see this as a specific problem. We now
16 understand that we need to at least address it. I
17 think these regulations do protect those children,
18 and I think this comes under my concern about
19 accountability and review of IRBs and having ways for
20 us to think about what good outcomes would be in this
21 process of review of human subjects research. But we
22 are willing to go through the examples and to see
617
1 where this would fit in these regulations. And if it
2 doesn't, then I'm in full and complete agreement that
3 we need to be as explicit as we can be to prevent
4 children from being hurt.
5 I mean, I don't want to be taken wrongly
6 to support hurting children. I mean, that has never
7 been anything that in my life I can remember having
8 advocated. So, I mean, I just want to be clear that
9 the working group didn't see this as a problem
10 because the working group, I would bet, I haven't
11 asked them each individually, would have believed
12 that this was covered in the regulations, not
13 uncovered and in need of specificity. But it doesn't
14 seem to be explicitly adequate addressed, so we need
15 to at least think about it and see where it might
16 fit.
17 Bob.
18 DR. R. LEVINE: I raised my hand a while
19 back while Judith was speaking. And I want to
20 partially disagree on technical grounds with one
21 thing she said. There's nothing in the regulations
22 for research involving adults that would preclude
618
1 taking a drug for research purposes that present risk
2 with no compensating benefit.
3 In the children's regulations there is
4 very clear explicit language that rules it out. I
5 think the way we could make Adil happy, if I
6 understand his unhappiness, is to say that as a group
7 we endorse, in general terms, section 406 of the
8 Subpart D. That's what rules it out.
9 DR. FLEISCHMAN: Adil.
10 DR. SHAMOO: I couldn't agree more with
11 Bob.
12 [Laughter.]
13 DR. R. LEVINE: [Off mic.]
14 DR. SHAMOO: He must be wrong, he said.
15 [Laughter.]
16 DR. SHAMOO: But that's exactly the point.
17 Thank you.
18 DR. R. LEVINE: Do you want us to endorse
19 Section 406?
20 DR. SHAMOO: With compliance. With
21 compliance and oversight. There's a big difference.
22 DR. FLEISCHMAN: Elliot.
619
1 DR. DORFF: I actually want to talk about
2 something else. Is that okay.
3 DR. FLEISCHMAN: It's okay with me.
4 [Laughter.]
5 DR. DORFF: First of all, he won't say it,
6 so I will. His name is Adil.
7 What I wanted to talk about was the last
8 line of Section 6 that you read. And when you read
9 it, you put in a -- of that draft is what we would
10 call it, in other words an interpretation. That
11 wasn't in the language and I don't know what you
12 mean. Okay.
13 And the alternative options including
14 palliative care are offered. What does that mean?
15 Does that mean they are offered instead of this Phase
16 I drug, or they're offered in addition to, along with
17 the Phase I drug? See, I would be much happier if
18 they were offered along with the Phase I drug.
19 DR. FLEISCHMAN: It depends on the
20 specific protocol. I would be much happier if they
21 were both offered along with and as an alternative
22 option so that families understand and accept the
620
1 reality of their dying child because almost every one
2 of these children will die shortly after they're part
3 of these trials. But that they really understand
4 then that palliative care without this altruistic
5 volunteering of their children is available. And
6 that palliative care within the trial is a mandatory
7 part of the IRB approval process.
8 The problem, of course, is that in some of
9 these trials the toxicities are so great that it's
10 very hard to alleviate any of the symptoms, even in
11 the hands of good palliative care people. So what I
12 meant in my commentary was that both really ought to
13 be available to families. They ought to honestly be
14 told in the consent form that this is purely
15 voluntary. Palliative care is available for their
16 children and the very best of humane care and caring.
17 But if they do get into the trial, then the
18 obligation of the investigator is to assure that as
19 best as possible the symptoms can be handled.
20 DR. DORFF: That's wonderful. I just
21 would ask you to make that a little bit more
22 explicit.
621
1 DR. FLEISCHMAN: Felice.
2 DR. F. LEVINE: Well, I can say I've
3 learned a lot. And I think my response is -- or the
4 issue I want to raise is really that irrespective of
5 what I was taking almost as a facetious proposal -- I
6 mean, to try to see if we could reach closure,
7 meaning that we really should take it up.
8 When I said I learned a lot, I mean,
9 really as obviously I come to this area as a somewhat
10 lay citizen with an interest in ethics, but not deep
11 knowledge of the nature of this kind of
12 experimentation. And as a member of the working
13 group I really saw nothing as off the table. I
14 really saw our first meeting as having, in a way, a
15 very specialized focus because we had a really -- a
16 mandate before us and indeed, at least the part that
17 I could participate in, up until about 12:30, we
18 couldn't do a lot of the brainstorming that we might
19 have otherwise done with some of these issues and I
20 think here and in the last issue that was just
21 raised, it's not just the consent forms, but these
22 are really threshold about the whole consent process
622
1 because these are not only vulnerable children, but
2 these are very vulnerable parents as we were talking
3 about yesterday. So how that consent process
4 unfolds, I think is a really key issue for this
5 working group because of the challenge that we face
6 with children at such medical risk.
7 DR. FLEISCHMAN: And I'm going to in a
8 moment to ask the public people, the ex officio
9 members and anyone else in the audience who would
10 like to make a comment to come to the microphone.
11 There will be some data about this consent
12 process that's being generated by an NCI-funded
13 project in the children's oncology group that's being
14 run out of Cleveland in which we are -- not we, but
15 they, are looking at the whole question of informed
16 consent and both the involvement of the investigators
17 as well as the families in this process. So we will
18 benefit, I think, from understanding more about that.
19 Greg and then if people will come to the
20 microphone to speak specifically about the issues
21 that you've heard us comment around.
22 DR. KOSKI: Just very quickly to add to
623
1 what Alan just said. There is actually a host of
2 research studies being done currently on the consent
3 process, much of that being funded by NIH through the
4 LC project which deals not only with children, but
5 with the elderly, with a whole host of different sort
6 of characters who might be asked to give consent and
7 the issue of informed consent is one that Secretary
8 Shalala announced back in June as being one of the
9 highest priorities that we need to take under
10 consideration and it's our full intent to put that on
11 the upcoming agenda for this committee. So you'll
12 have an opportunity to attack that head on.
13 Thank you.
14 DR. F. LEVINE: Could we get a list of the
15 abstracts of those studies just so that we can see
16 what's underway? Assuming that they've been funded.
17 DR. KOSKI: Right. These studies I only
18 know about them because I served on the advisory
19 committee as a consultant that recently reviewed some
20 of the progress reports on those. I don't know the
21 status of publication, but I would be happy to check
22 into that and report back to the committee. My guess
624
1 is that these investigators would be more than happy
2 to share the results with anybody who is willing to
3 listen.
4 DR. FLEISCHMAN: I see no commentators,
5 but I'm looking. Please. Introduce yourself and
6 give us your comment.
7 MS. OLSTER: My name is Deborah Olster,
8 I'm a AAAS fellow working at the NSF. But my comment
9 is coming from my other life which is as a
10 physiologist. And what I've heard in this discussion
11 is that depending on how you use a particular
12 chemical, you may be calling -- it may be a drug or
13 it may not. And if whatever document you produce
14 comes down to that issue, you may want to consider
15 just using some language to define what you mean by a
16 drug and it might clarify things for people.
17 DR. FLEISCHMAN: Thank you.
18 Let me see if I can conclude -- oh, I'm
19 sorry. Go ahead. Introduce yourself, please.
20 MR. GRAVE: Gilman Grave from the National
21 Institute of Child Health and Human Development. I
22 think that people use Phase I studies to mean many
625
1 different things, and I think we ought to get a nice
2 definition that the whole committee can agree on.
3 I've heard Phase I studies being called safety
4 studies or toxicity studies. I've heard them called
5 PK studies. I've heard Phase II studies called dose
6 ranging studies with efficacy in the small group.
7 And then I've heard Phase III, of course, called
8 efficacy. So I really think that Judith might be
9 very helpful here and Dr. Roberts, because I think we
10 really need a very precise definition of what we're
11 talking about as Phase I.
12 It's such a flexible yardstick in our
13 current discussion.
14 DR. FLEISCHMAN: Thank you.
15 Introduce yourself, please.
16 MS. SHEROV: I'm Vera Sherov and I'm
17 president of CRCR Care, many of you know about it.
18 Citizens for Responsible Care in Research. And I
19 would like to not comment on what you were talking
20 about now, but rather to make a statement which is a
21 bit of a distillation of comments that we submitted
22 to the Office of Human Research Protections. And it
626
1 deals a great deal with normal children, healthy
2 children and what's to be done with them. And also
3 it deals with why this very panel was called in the
4 first place -- was convened.
5 The basic question, and I know that you've
6 heard it from Adil quite a bit, is now in a broader
7 sense, not Phase I, not oncology. Who has the moral
8 authority to volunteer children for drug trials that
9 are likely to be against their best interests?
10 That's the question the public wants to know.
11 Now, we think that federal policy, until
12 now, has been to protect children from non-
13 essential, invasive, painful, medical experiments.
14 Regulatory restrictions were adopted to prevent the
15 inclusion of children in experiments that involve
16 greater than minimal risks and no prospect of direct
17 benefit to the individual subject.
18 We are alarmed by recent policy changes,
19 both by the FDA and NIH which essentially opened the
20 gates to the exploitation of children in medical
21 experiments that are likely to cause them pain,
22 discomfort, and put them at risks of harm without
627
1 medical justification.
2 In 1997 when Congress extended patent
3 rights for pharmaceutical companies to test drugs on
4 children, they were not informed that the system of
5 protections was broken.
6 As Dr. Marshall stated -- wrote, actually,
7 since 1990, the research climate has worsened
8 dramatically. Federal investigations since 1998 made
9 clear that non-compliance with ethical standards and
10 federal regulations was widespread. Research at six
11 institutions was shut down. All federally funded
12 research was suspended at another three institutions.
13 From January 1st, '99 to June 2000, approximately 60
14 institutions, including some of our most prestigious
15 universities were found non-compliant.
16 Since July 2000, OHRP has suspended
17 federally funded clinical trials at seven additional
18 research centers.
19 In her waning months in office Donna
20 Shalala wrote, "I did not expect or want to complete
21 my tenure as Secretary of Health and Human Services
22 by raising questions about the safety of patients in
628
1 clinical research. However, recent developments
2 leave me little choice."
3 Dr. Koski acknowledged the system may have
4 gotten entirely out of control and might have to be
5 reorganized. We must take steps to reestablish the
6 public's trust in the goodness of our endeavor.
7 Given this unsettling climate, we are
8 dismayed, the children are being aggressively
9 targeted.
10 The questions posed by OHRP reveal to us
11 ignorance about the full-blown crisis. These
12 questions presuppose an existing functional system of
13 protections for adults which one is led to assume
14 needs only slight modification for children. But
15 that presumption is totally insupportable by the
16 weight of the evidence demonstrating systemic
17 failure. At this time the system cannot even assure
18 that autonomous adults are safe, thus we believe that
19 it is irresponsible to broaden the recruitment of
20 children.
21 According to the New York Times between
22 1991 and '96 there were 11 pediatric studies; 16,000
629
1 children were subjects in 1996. Now children are
2 being catapulted into clinical trials, becoming means
3 to increase profits.
4 The Boston Globe reports that the drug
5 industry is spending $1 billion a year on pediatric
6 testing. Forty-five thousand children are
7 participating in medical experiments this year.
8 Researchers are getting bountiful
9 financial incentives, 5,000 is not unusual to recruit
10 children.
11 Thousands of healthy children are being
12 sought to serve as drug testing subjects with
13 monetary bribes to their parent, kickbacks to
14 doctors, and patent extensions to drug manufacturers.
15 Without adequate safeguards children are
16 fast becoming casualties of the broken system. The
17 disastrous FDA-approved propulsa [ph] trial is a case
18 in point. Infants were recruited to test a drug that
19 had already killed adults and children. Experimental
20 eye surgeries at the University of South Carolina
21 caused more than the usual complications including
22 transplants that slipped and wounds that broke open.
630
1 The Globe reports that a toddler was
2 subjected to a self-contained experiment in which
3 traditional surgery was performed on one eye and a
4 new technique on the other resulting in unusual
5 bleeding into the eye.
6 Another case involves a pacemaker
7 experiment at NIH that killed an 11-year-old and
8 caused the condition of a 12-year-old to deteriorate
9 badly.
10 This government agencies refuses to
11 provide public information about the outcome of that
12 pacemaker experiment including the number of children
13 helped and harmed
14 Government lawyers at NIH shield doctors
15 from accountability. Now, if answers are not
16 forthcoming the public's outrage will be directed far
17 and wide, not just at the wrongdoers. Will this
18 committee follow up and try to get answers?
19 Unethical research practices are not
20 anomalies. They are a consequence of the
21 inextricable conflicts of interest that have lead
22 researchers to subordinate the health and welfare of
631
1 human subjects for financial interests and helpless
2 children are becoming the sacrificial lambs.
3 No one keeps track of adverse events in
4 pediatric or adult research. Even industry
5 consultants acknowledge, and I quote, there are some
6 time bombs out there and we don't have the
7 infrastructure to monitor research from end-to-end.
8 CIRCare strongly urges mandatory reporting
9 of adverse events to a federal database for keeping
10 track of above-minimal risk research involving human
11 subjects.
12 Some clinicians who had pushed Congress to
13 widen the inclusion of children not anticipating the
14 unintended consequences are now concerned about the
15 lack of professional restraint.
16 Robert Ward of the American Academic of
17 Pediatrics is quoted as saying, "We've heard of drug
18 studies being conducted in motels, in which they rent
19 a block of rooms, they're not provided with equipment
20 to deal with complications and allergic reactions.
21 Are there no mandatory requirements to ensure ready
22 access for emergency medical interventions wherever
632
1 human research is being conducted? Is there such a
2 regulation? Who is responsible when things go wrong?
3 We agree with one statement in the
4 subcommittee's report, and I quote: "Research
5 funder, industry, institutions, investigators, and
6 the public share the responsibility for assuring
7 research is performed in an ethical manner."
8 However, we believe that without mandatory safeguards
9 and independent checks and balances to enforce them
10 vulnerable people, most especially children, are not
11 safe.
12 Dr. Koski acknowledged on CBS 60 Minutes
13 that the federal protection system depends on
14 whistleblowers after the fact. Uninformed consent,
15 the copiously documented series in the Seattle Times
16 demonstrated the same thing as it reported systemic
17 failure to protect research subjects.
18 Clearly the evidence demonstrates that
19 self-regulation has fostered a climate of self-
20 interest. It may protect deviant investigators in
21 institutions, but it fails to protect vulnerable
22 patients from abuse, exploitation, and harm.
633
1 CIRCare believes that existing regulatory
2 restrictions need to be enforced and strengthened to
3 protect children from medical predators.
4 Instead, we are concerned about the draft
5 policy and procedures for DHHS research involving
6 children 45 C.F.R. 46.407 which was revised March 12
7 of this year, because it redefines and weakens
8 current regulations that had been adopted to protect
9 healthy children from exploitation.
10 The draft policy would broaden the
11 criteria under which healthy children may be
12 subjected to risky research by inventing a new
13 category. Risk bearing children, what are risk
14 bearing children? And by redefining the terms,
15 "disorder" or "condition" and "reasonable
16 opportunity."
17 The DHHS indicates that for the purpose of
18 Section 46.406 the term "condition" is redefined to
19 include non-medical conditions including a
20 demographic descriptor. Does that legitimize racial
21 profiling?
22 Whatever the condition, the children are
634
1 being used to test medical interventions. By
2 twisting regulatory terminology, federal policymakers
3 would legitimize experiments that put healthy
4 children at risks of harm without scientific
5 justification or potential benefit. I will cite
6 three examples. One was fenfluramine experiment
7 which we do return to over and over because it was
8 never clarified, is it legal or not.
9 And then there was the NIH obesity study
10 which was shut down by OHRP in which 93 healthy
11 children were exposed to pain, discomfort, risks,
12 with the preposterous justification that the research
13 was, quote, safer than playing actively on sidewalks
14 and streets.
15 And then there's an Eli-Lilly experiment
16 at Yale that is exposing 32 children and adolescents
17 to serious risks of adverse side effects associated
18 with the company's powerful schizophrenia drug,
19 elanzopine to test a hypothesis.
20 The experiment has been widely criticized
21 even by NIMH researchers and by the leading proponent
22 of schizophrenia prevention research in Australia.
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1 Dr. Patrick McGory [ph] is highly critical of
2 researchers both at Yale and Harvard for conducting
3 this experiment. He told Time Magazine, current
4 issue, "the Americans went at it like a bull at a
5 gate dispensing antipsychotic drugs to adolescents on
6 unacceptably flimsy grounds." We strongly disagree
7 with this DHHS proposed policy change and ask whose
8 children will be designated, "risk bearing" children?
9 What is the ethical and scientific
10 justification for a government oversight agency to
11 redefine existing regulations so that safeguards for
12 children are effectively diluted rather than
13 strengthened. This ill-advised policy is encouraging
14 the recruitment of thousands of helpless children
15 exposing them to drugs whose safety has not been
16 established. Whose children are being sought for
17 these painful, potentially harmful experiments?
18 And do those who profit from drug trials
19 volunteer their own children for science?
20 Also the proposed changes, is this a
21 notice of intent to regulate because then it would
22 require that it be done in accordance with federal
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1 administrative procedure act, otherwise those
2 recommendations would be nullified if accepted.
3 DR. FLEISCHMAN: We'd appreciate receiving
4 those comments if you would --
5 MS. SHEROV: Yes, I have the fuller ones.
6 DR. FLEISCHMAN: Give those to us so that
7 we can digest them more carefully.
8 The workgroup actually has several
9 concerns that parallel yours and in concluding this
10 part of the conversation about the workgroup's
11 report, the workgroup actually is concerned about the
12 importance of aggregating information about adverse
13 effects. The importance of coordinating the work of
14 DSNBs and IRBs for the benefit of children as
15 subjects. And would very much like that to be part
16 of the discussions of this group. It's not child-
17 specific, but is an important part of monitoring
18 adverse occurrences, and also the workgroup on
19 children is also interested in looking toward
20 additional monitoring of research studies of IRBs and
21 meaningful oversight of IRBs.
22 We've said that several times, and in the
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1 course of the conversation that the IRBs do require
2 accountability, oversight and review and in order to
3 do that, we are going to have to be very creative in
4 terms of what are the outcome measures to look at.
5 How do we ensure that investigators and IRBs are
6 doing their jobs which is part of, I think, what
7 you're really talking about from a --
8 MS. SHEROV: I am, but I think that part of
9 the problem that has come out everywhere where there
10 is a scandal, everywhere where there is a shutdown is
11 that the IRBs clearly cannot do it themselves,
12 particularly when some of the people that they're
13 supposed to oversee are far more powerful than they
14 who bring in the grants. I mean, we are quite
15 cognizant of reality and money is important. I know
16 that Greg has often said that one should take the "I"
17 out of the IRB and call it a research protection --
18 what would you call it, RRB? Research review board.
19 Okay. Research review board. In other words, not
20 based in the institution who studies are being
21 evaluated. That come across very clearly from IRBs
22 and I hear a great deal from people in IRB.
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1 DR. FLEISCHMAN: I will conclude our
2 workgroup report by remind the committee that the
3 workgroup believes that there ought to be specific
4 memoranda on a series of issues to clarify the
5 present regulatory structures to give examples. And
6 we've listed a whole host of those which we've had an
7 opportunity to talk about most of them today. And
8 the workgroup remains prepared to address other
9 issues as well as these and to help the committee in
10 developing some of these memoranda if the committee
11 so wishes.
12 And I will turn it back to our
13 chairperson.
14 DR. DORFF: Just a question. The changes
15 in the definitions of 406 and 407 to which you
16 alluded, is that -- first of all, that's not coming
17 from this committee, so where is that coming from and
18 that's not the document that we got, I take it? I
19 mean, I'm just perplexed.
20 DR. KOSKI: There are no changes.
21 DR. DORFF: Oh.
22 DR. SHAMOO: There is an advisory from FDA
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1 how to reinterpret 407. There was an FDA ethics
2 advisory --
3 CHAIRPERSON MARSHALL: Adil, let me
4 clarify that because I actually sat on that, what is
5 called a 407 panel. I guess in the many years since
6 the regs have been in effect, there have not been
7 many 407 panels convened or called. Requests have
8 not come from local IRBs to look at research that
9 potentially would be approveable under the 407 area.
10 There was a group of special consultants
11 to the OHRP that was asked to look at some studies
12 that may potentially have been approvable under the
13 407 regulations -- component of the regulations. And
14 the outcome of that was that the group did not review
15 any of the studies that were proposed, the group felt
16 that there was not an adequate framework for IRBs to
17 use to put studies forward, and for them to be
18 evaluated at the local level and that there was work
19 to do at the policy or the interpretation level. So
20 there was a draft document that I believe is on the
21 web; is it not?
22 Yeah. And it's in our notebooks. And,
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1 the working group on children used that to inform its
2 thinking in terms of the request from the Department
3 of Health and Humans Services to assist them in
4 responding to the Child health Act or the request for
5 response to the Child Health Act. So there is
6 nothing that has been official in terms of any
7 changes to the regulation or any policy that has been
8 adopted by the OHRP. This document that was put
9 forth by the 407 panel, as far as my understanding
10 that the only use that has been made of it is that it
11 has been forwarded to our working.
12 DR. SHAMOO: That's not the one, Mary, I'm
13 talking about. People in FDA can correct me. If you
14 go to the FDA web site, there was a new, in the past
15 few months, FDA ethics advisory. A group of
16 ethicists got together to explain how the 407 will be
17 -- and I don't know, we are across purpose we are
18 talking.
19 They are the one who mentioned the word
20 "otitis media" is that the one? That's the one they
21 said, every child, therefore, can be considered sick
22 because they will get otitis media. Therefore any
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1 drug for otitis media -- that is the example they
2 used -- any drug for otitis media can be tested on
3 healthy children because in the future they will get
4 otitis media. That's -- I got it out of the web
5 site. None of you know anything about it. Sorry.
6 CHAIRPERSON MARSHALL: Rosemary, could you
7 please speak to that for us? Because I'm confused,
8 I'm not sure what the facts are.
9 DR. ROBERTS: Okay. There was a pediatric
10 advisory subcommittee meeting in November of 1999
11 where there was a discussion about the use of healthy
12 children volunteers in non-therapeutic trials. And
13 basically after a discussion by a panel of six
14 ethicists, it was concluded, and their advice was,
15 that children who have the disorder or the illness
16 should be the only ones who participate in the trial.
17 Or, if they are likely to get the condition.
18 Now, for otitis media, the one time they
19 said the trial designed, or the trial that we
20 described that they agreed young children -- in this
21 country almost every child will get at least one
22 episode of otitis media.
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1 So the trial example that we put up was a
2 single dose taste test of a new antibiotic and it was
3 agreed by those people who deliberated, that they
4 felt that kind of a single dose as a taste test on
5 healthy children who are likely to have an episode of
6 otitis media they could find that acceptable.
7 But basically nontherapeutic trials are to
8 be done in check who have the condition.
9 DR. SHAMOO: I'm glad that you confirmed
10 that there is such a thing -- and we didn't -- Abbey
11 and I didn't make it up. And although otitis media
12 was used an example which opens the door for other
13 type of examples that can be used to broaden the
14 definition. That is a problem.
15 MS. KORNETSKY: I was at that meeting and
16 participated, now that I understand what it is. And
17 I have to say that there were other -- several other
18 examples that were not, you know, permitted and there
19 was quite a bit of discussion. I don't think that
20 was totally unanimous from my own standpoint.
21 [Simultaneous conversation.]
22 CHAIRPERSON MARSHALL: We have asked, and
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1 we really do need to move along because Felice has
2 been very patient with us.
3 Adil and Abbey, I would ask and invite you
4 to, one, help us with the task that we talked about
5 earlier relative to the concrete examples that the
6 committee -- that the workgroup -- sorry -- can move
7 forward with. If there are other things that you
8 would like for us to move forward with, then please
9 let us know. And Greg would like one final comment
10 and then we're moving on.
11 DR. KOSKI: I would just like to thank all
12 of you for your thoughts and input. Clearly this is
13 an area that not only is very complex, but can be
14 very emotionally charged as we think about those that
15 we love so much.
16 Our office is charged with putting
17 together, as I mentioned earlier, a report to
18 Congress in response to the Child Health Act of 2000,
19 and so I would urge this group to offer to us its
20 advice at its earliest possible convenience.
21 We intend to incorporate the advice from
22 NHRPAC along with advice that we've received from
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1 other individuals, other organizations, that have
2 been broadly solicited across the country and will
3 make first an initial report to Congress that we
4 expect to deliver sometime around the first week in
5 May, and will then ultimately be following up with an
6 additional report. Clearly when and if it comes time
7 to issue either new policy or change regulations we
8 will, of course, go through the appropriate notice of
9 proposed rulemaking with public comment and so on as
10 is routine and customary for that kind of government
11 business.
12 But I just want to thank the members of
13 the workgroup and the members of the public, members
14 of the committee at large, and particularly to Dr.
15 Fleischman for his leadership in this. I'm sure
16 we're all going to benefit enormously from it. Thank
17 you.
18 CHAIRPERSON MARSHALL: Thank you, Greg.
19 And I would like to second your thanks to Alan and
20 the other members of the working group. We have just
21 begun and I think that was how Dr. Fleischman began
22 his remarks in his conversation. Our group has only
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1 had the benefit of one meeting.
2 So, we truly have just begun. And thank
3 all of you for helping to inform our thinking today
4 and as we move along.
5 Felice, would you like to come to the
6 front, or are you happy to --
7 DR. F. LEVINE: [Off mic.]
8 CHAIRPERSON MARSHALL: Thank you.
9 DR. F. LEVINE: We're going to run to
10 about 6:30 this evening, right?
11 [Laughter.]
12 DR. F. LEVINE: Well, we heard Alan say,
13 looking to the agenda, actually, that the children's
14 working group is a work in progress which sort of
15 took the words out of my mouth and you could see how
16 productive that work in progress was. I would say
17 that we too are a work in progress and at this moment
18 really what we want to do is really give you an
19 overview of where we're going, not where we've been
20 because we've just begun.
21 I hope that those of you who didn't pick
22 up the report, I think there are -- needless to say,
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1 one of the hot pieces of paper to take back to your
2 homes, copies of the report that we prepared on the
3 social and behavioral science working group and I
4 think what we want to do today is just give you the
5 briefest overview of where we are and what we see
6 ourselves doing.
7 And really to sort of solicit comments,
8 advice, guidance, in particular, by e-mail at this
9 hour because I know there are a number of important
10 issues we want to get to on the agenda.
11 My co-chair, as Greg alluded to, there's a
12 hardworking group of federal officials seeming to be
13 constantly in the air advising, speaking, lecturing,
14 educating, and Jeff Cohen is the director of the
15 education division and he is absolutely phenomenal
16 and so he's here, but you don't see him. But he's
17 been very much a presence. Indeed, we count
18 backwards when he's in Hawaii and we plug him into
19 conference calls and he is -- he's just been on the
20 road a huge amount because the work that is underway
21 is rather labor intensive on human subjects issues
22 more broadly and certainly the education division is
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1 playing the leadership role in that regard.
2 I am joined, happily, by my colleague, an
3 ex officio member of the committee, Phil Rubin, who
4 is the NSF division director of the Behavior and
5 Cognitive Science Division. And he also is an active
6 -- I'll say participant -- in the subcommittee on
7 human subjects research protection on the Committee
8 on Science. And I guess is chairing the social and
9 behavioral science subcommittee.
10 And one of the things that we want to talk
11 a little bit about is that interaction between the
12 agencies that fall under the common rule and the
13 interaction between the Committee on Science and the
14 subcommittee on Human Subjects and how we are working
15 together to integrate and glean the best set of
16 wisdom and knowledge.
17 I'm not going to repeat the outline, but
18 very much the charge of the working group really
19 emanated from this group, from the advisory committee
20 in December when I spoke to the advisory committee
21 about the common rule, the guidelines for the
22 protection of human subjects and the history of
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1 experience with the social and behavioral sciences
2 with those rules, and both their workability and
3 their complexities really much more in their
4 implementation than necessarily the language on
5 paper.
6 And we saw as the charge in discussions
7 with Mary Faith and Kate Louise to develop guidelines
8 to help institutional review boards and I would say
9 the Human Subjects Protection System more broadly
10 reviews social and behavioral science research
11 involving human subjects and as we talked about over
12 the past two days, also to certainly not foreclose in
13 any respect, but not necessarily be led by the notion
14 of any change, per se, in the regulations, to of
15 course entertain and ask ourselves whether in
16 specific language or forms of transformation we may
17 need to make recommendations regarding additions or
18 changes with respect to the rules insofar as they
19 need to be better appreciative of the full range of
20 research that involves human participants. Not
21 because there are another set of rules, but because
22 the language that has often been used has evolved
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1 much more in the context of biomedical research.
2 And, therefore, by illustration and
3 example we may need to develop materials that better
4 communicate both to social and behavioral scientists
5 as well as to those involved in the review process.
6 The composition of our working group and
7 all volunteers are welcome, and I guess this in a way
8 speaks to the housekeeping discussion that we will be
9 having subsequently. But the composition of the
10 working group is currently 12 strong. Three members
11 of the committee, Dr. Jennie Joe who couldn't be with
12 us today, who bring a strong interdisciplinary
13 background, as I think many of us around the table
14 indeed do in public health and nursing and in
15 anthropology.
16 Dr. Jonathan Moreno who stepped forward
17 and volunteered to be part of this -- I think --
18 ambitious enterprise. Seven ex officio agencies, not
19 necessarily always the ex officio members, but from
20 the ex officio agencies, and you have a list in the
21 back.
22 And I'll give you an example of what we
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1 were seeking to do and that is from the Department of
2 Justice, Dr. Sally Hillsman who is the Deputy
3 Director of the National Institute of Justice with a
4 long career as a very active bench scientist doing
5 work on various aspects of crime in the
6 administration of justice. And we were seeking in
7 this working group to be strong in the talent pool of
8 persons who have wrestled with the difficult and
9 complex issues of reviewing research which she
10 certainly is now involved in doing, undertaking that
11 research, working with subjects in different forms of
12 vulnerable populations and bringing that best wisdom
13 to bear.
14 So the seven agencies which are ex officio
15 colleagues, the three of us from this committee and
16 two active members of the research committee that --
17 research community that don't bear any of those hats,
18 one is Dr. Joan Sever who is at California State
19 University with a long-term set of experiences in the
20 ethics of research and human subjects protection.
21 And people are shaking their heads yes. And I feel
22 like I've known Joan my whole life in this area which
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1 is several decades and I think anyone who is
2 intersected with these issues do, and not only does
3 she bring the sophistication as a quality scientist,
4 psychologically trained, but also -- and the
5 longstanding interest in human subjects protection,
6 but a lot of interaction around IRBs and experience
7 with IRBs, and in particular some very active work on
8 issues of accreditation and other similar issues with
9 Primer.
10 And the other is Dr. Robert Hauser who is
11 at the University of Wisconsin Madison at the Center
12 for Demography on Health and Aging who has been a
13 very active primary researcher in issues that relate
14 to health and well-being of children, also the
15 education system and has had wide experience both
16 with extant data collections as well as the producer
17 of primary data including longitudinal data.
18 And we thought through that composition,
19 not to be exclusive, but to really be inclusive of
20 the range of methodologies and strategies that come
21 into play in doing quality research and in working
22 with human participants in a variety of experiences
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1 and with a variety of intersections from the mere
2 observation of people in public places to lab
3 experiments to field experiments, et cetera.
4 Our hope is to -- I think one of the
5 things we have to control ourselves from doing as
6 social and behavioral scientists are those of us who
7 identify with these fields is not to make this a
8 research project.
9 [Laughter.]
10 DR. F. LEVINE: And I must say, my
11 constant interaction with Mary Faith and the e-mails
12 about this, because, of course, this is for us, a
13 lively subject. You know, everyone would love data
14 and what better subject to study than the human
15 subjects protection system. I think that's phase two
16 of the IOM study.
17 And we are seeking to bite the bullet and
18 I will say, be instrumental, build upon the best
19 knowledge that exists, and do it in a very wide open
20 and transparent way. So we are going to have town
21 meetings and discussions at various research
22 societies. We're going to be going to the Primer
653
1 meeting and trying to get input from a variety of
2 professionals in a variety of ways. Indeed, in my
3 own head I'm trying to think about how, without
4 creating undue additional burden. We even have some
5 input from persons who were subjects in a variety of
6 different types of studies, studies that have been --
7 have been concluded and how we can work in that way.
8 Also, it would be very important when we
9 talk about access to public data and data sets that
10 have been made publicly available to talk with some
11 of the leading person in the social and behavioral
12 sciences we have some quality data archives and data
13 repositories and how some of those complex issues are
14 resolved when we're talking about deep interviews
15 with small samples, and under what conditions is
16 access provided.
17 And so the Murray Center for the Study of
18 Human Lives, the Interuniversity Consortium of
19 Political and Social Research provide for us
20 opportunities to build upon expertise and I don't
21 know if I should use the language "exploit it" but
22 capitalize on it so that we can move in a fast and
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1 deliberative way and I hope you'll see the fruit of
2 that.
3 At the July meeting we're going to have
4 our first official meeting of the almost full group.
5 On May 16th we had a mini meeting talking -- thinking
6 through the logistics and the operation and sketching
7 forth the issues that we want to be able to address.
8 And I don't want to repeat in any sense the outline,
9 but if you scan the outline, you will see an outline
10 of the substantive scientific issues that we see as
11 central to grapple with, with respect to the social
12 and behavioral sciences from issues of risk to what
13 constitutes, as we talked about yesterday, what
14 constitute human subjects, what constitute
15 interaction, issues of concent, at what process, and
16 assent and with what process and what staging.
17 Complex issues involved in different forms
18 of research from longitudinal study to non-invasive
19 experiments to international research and how we --
20 and how the system is currently operating, how
21 researchers are currently understanding it and how we
22 both have successfully, and sometimes more complexly
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1 navigated the human subjects protection system.
2 So I really see this, for all of us, as a
3 kind of a collaborative opportunity because there
4 isn't one person around this table that -- this table
5 and those chairs that can add to the process. And I
6 think we all look forward to the evolution of how we
7 present the Human Subjects Protection System in a way
8 that truly not meets the needs, but truly
9 communicates its adequacy for all forms of research
10 involving human subjects protection.
11 Most of us involved in this process for as
12 many years as some of us have been recognize that it
13 both can and has done so. And where we need to look
14 toward is identifying those areas that have been more
15 complex, that have been less workable and trying to
16 address those challenges in a way that when that
17 system presents itself, it truly communicates
18 effectively.
19 The one hand out that I have, and I have
20 extra copies at the end of that table, is three
21 charts from the Office for Protection for Research
22 Subjects. And I think they are generically useful.
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1 But what they help us do in the social and behavioral
2 sciences is identify what have been some of the
3 traditional fault lines.
4 One we really talked about yesterday
5 afternoon quite a bit. And that is what constitutes
6 human subjects? And what constitutes private
7 identifiable data with respect to those human
8 subjects and that's chart 1.
9 Chart 2 is, is the research exempt? Will
10 the research use solely-existing data or specimens?
11 And currently we have some complexities in the social
12 and behavioral sciences with respect to IRBs seeking
13 to review data that are essentially public-use files
14 that have already been debited as public use files
15 through IRBs. And so we have a mutual education.
16 What happens when someone is looking at the yes
17 column versus the no. And when do they identify yes
18 versus no?
19 Similarly, what does it mean, intervention
20 and interaction in chart 1. if one is observing
21 essentially an anonymous form, human interaction in
22 public places and there is no intervention or
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1 interaction between the researcher and those being
2 observed. Is that in the no column which is
3 traditionally the case, I might say, but currently
4 the case under the fragility of the system, more
5 typically finds itself in the yes collection. That
6 can have rather challenging consequences for
7 ethnographic studies where indeed there's no intent
8 for interest in being in any way altering the
9 environments or the experiment.
10 And similarly the issue of waiver, I think
11 is similarly important. And what we want to work
12 through is examples and be able to provide not only
13 insights and information, but I think some guidance
14 as to best practices that ideally will be extremely
15 helpful to those IRBs, perhaps less experienced with
16 social and behavioral research, and also to those
17 researchers who sometimes may wonder how, indeed,
18 they need to deal with certain of the vital choice
19 points that they may not be sufficiently cognizant
20 of. And so a lot is going to go on between us.
21 I want to turn this over to Phil who will
22 give us another angle, but it's a collaborative
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1 angle, and I think that is the strength of what we're
2 seeking to do together.
3 DR. RUBIN: Hi, my name is Philip Rubin.
4 I'm the Director, Division of Behavioral and
5 Cognitive School at the National Science Foundation.
6 That means I'm responsible for programs that range
7 from cultural anthropology through the new children's
8 -- congressionally mandated children's research
9 initiative to the new cognitive neuroscience program.
10 In addition, I'm the NSF ex officio. And, finally,
11 I'm the chair of a committee that's part of the Human
12 Subjects Research Subcommittee.
13 A couple points I want to emphasize is I
14 see my role there as one of communication. That's my
15 job and it's a complex job because there are a number
16 of agencies. The HSRS is an interagency group and
17 there are concerns across agencies. The goal is
18 protecting the participants in research. However,
19 there's a diversity of approaches. I want to
20 emphasize though that the group is called behavioral
21 and social science. The real issue from my
22 perspective is non-biomedical research.
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1 There are a variety of agencies, as I
2 said. There is the Department of Energy, the
3 Department of Justice, and there are unique concerns.
4 What we need to do across the agencies is try to
5 identify what are the special issues in the agencies
6 in terms of what their concerns are, and in what they
7 need to do to best protect participants. So, in a
8 nutshell, what we are trying to do is identify those
9 issues by working with the individual agencies and
10 finally eventually bring a report to this particular
11 group that hopefully will have some guidelines that
12 are concrete and to try to do that as rapidly as
13 possible. It's very difficult working across a lot
14 of agencies, but to try to do that rapidly.
15 We are encouraging the other agencies to
16 follow our model. What we are doing at the NSF is in
17 May we're having a workshop, we're bringing people in
18 from a wide variety of interests and areas to try to
19 grapple with these issues and then report back. And
20 we're going to make sure we try to include
21 participants in research in addition to researchers
22 and administrators. There's a whole spectrum of
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1 interests, ideas, and issues.
2 Those issues, as Felice has stated, are
3 really broad. They range from things like
4 confidentiality, to issues of what is -- what exactly
5 is informed consent. A final issue -- and then I'm
6 going to turn it over -- that we grapple with is
7 because we also fund a lot of international
8 collaborative research we want to, at least from our
9 perspective at the NSF, make it very clear that there
10 are a lot of varying international and cultural
11 concerns. How we work with individuals and groups
12 has to be a joint effort and it has to be an effort
13 in which we're informed by those individuals that are
14 going to engage in the research process about what
15 their needs and concerns are.
16 And, finally, the regulations then or the
17 guidelines that are proposed have to reflect those
18 concerns. So we'll try to do that and pass that
19 information on to this group and we invite any agency
20 that is not participating to get in touch with us.
21 We have a list serve that we're running. We have a
22 workshop that we're holding and Stu Platner, who is
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1 the main person doing the work, would be glad to hear
2 from you and if you need to find out how, I'll be
3 outside after the meeting to give you my business
4 card.
5 Thank you.
6 CHAIRPERSON MARSHALL: I think that we
7 have time for some questions for Felice.
8 Let's do this, in terms of procedure. Why
9 don't you take 15 minutes for question and I promise
10 that all of us will be -- at least the meeting will
11 be over at 4:30. Whether all of us leave at 4:30 is
12 another thing. But we will finish at 4:30. I know
13 there are flights.
14 Thank you, Phil, very much for your
15 remarks. And I want to add on and make sure that
16 it's understood that the invitation that was extended
17 is also extended to our public members in terms of
18 participation.
19 DR. DORFF: What I'm about to say may be
20 completely unrealistic. Certainly from the
21 presentation that you made in December, and from the
22 paper that we read from the American Association of
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1 University Professors, at least I had the impression
2 that the common rule was sort of a *percustian bed
3 into which you found yourselves and that you needed
4 to somehow make the most of it. And I sort of had a
5 sense that this was really imposed on you and that
6 you were -- and that what the AUP, at any rate, was
7 doing was trying to say, "no, but" you know this that
8 and the other thing.
9 What I'm wondering, and that's one of your
10 goals, right, in other words to talk about, as you
11 put it, to make specific recommendations regarding
12 additions or changes to the common rule rather than
13 to the social behavioral sciences. And politically
14 that might be the easiest thing to do. But what I'm
15 wondering is, what would happen if you sort of
16 thought out of the box and were trying to create the
17 ideal world in which social science researchers
18 should be operating, vis-a-vis and including the
19 regulations to protect human subjects.
20 And the reason why I ask this is because
21 you would not be the first ones to think of this.
22 Presumably -- I mean, one of the things that you list
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1 as information useful to obtain is, are the ethical
2 guidelines of scientific studies of societies in
3 social and behavioral sciences. So presumably other
4 people in the various social sciences have thought
5 about this issue. And it would be sort of
6 interesting to see -- I mean, I thought in particular
7 that was really important, to see, you know, people
8 who -- you know, we're not thinking government and
9 we're not thinking common rule, we're not thinking
10 all of the law, we're thinking ethical guidelines.
11 And it would be interesting to see if
12 there are major distinctions between what they
13 thought would be reasonable moral rules to govern
14 social sciences as opposed to what the government has
15 thought to be reasonable rules.
16 Now, it may turn out that they're all the
17 same, or that they're very similar in which case,
18 fine. But if they're not, I would urge you to, you
19 know, not to be timid in this. But rather to -- you
20 know, to really state the things -- state the way
21 that it ought to be in order to do best kind of
22 research that social scientists can do. Because
664
1 after it's all said and done, that's what serves all
2 of our interests.
3 DR. F. LEVINE: Those are challenging
4 questions. I promise not to be --
5 Let me also say -- a new hat -- not the
6 hat of a committee member, although that too, that I
7 was presenting the AUP report and very much central
8 that AUP report was a strong interest, although the
9 language specified that it was talking about the
10 social sciences. A lot of it was really grounded in
11 the humanities. And that was in part some of the
12 social scientists in that group and myself included
13 were really brought to the group to really kind of
14 create some synergies between the social and
15 behavioral sciences that had much more history of
16 experience with the human subjects protection
17 guidelines and system, and those traditions of
18 scholarships including, and especially those that
19 really didn't fall under the common rule, in part,
20 because much of that scholarly work had fallen within
21 the traditions of NHA funded which is not one of the
22 agencies.
665
1 Now, from the social and behavioral
2 science point of view, which I thus was trying to
3 walk two lines in December -- this isn't a new
4 system, this isn't a *prescrestian system that indeed
5 we've been plopped into, the social and behavioral
6 scientists, from the outset, we're really a part of
7 the system.
8 The system itself, however, just in terms
9 to the sheer magnitude of the numbers of grantees and
10 the dollars of funding and its origins being much
11 more concerned about the troubled cases of medical
12 experimentation, et cetera, that much of the way it
13 operationalized in examples not ethical guidelines,
14 per se, but in examples and in rules of thumb were
15 much more grounded in the experience of the
16 biomedical sciences. And, indeed, the infrastructure
17 tends to be much more dominated by the biomedical
18 sciences including the IRB's.
19 So that what we have and what I was trying
20 to address in December, though it was probably
21 clearer in my testimony before IOM when I talking
22 about the Institute of Medicine in January when I was
666
1 talking about the social and behavioral sciences is
2 that we don't necessarily have a set of principles
3 that are workable, indeed I have advocated on behalf
4 of the common rule when faced with various efforts to
5 fly in the face of those principles on other
6 occasions; as I referred to the Family Privacy
7 Protection Act that would have essentially regressed
8 in its process by which parenteral consent was
9 obtained in it having an absolutely one-size-fits-all
10 solution and not permitting any kind of process by
11 which you could undertake research on adolescents or
12 on children and youth without a written parental
13 consent. And we invoked the history of experience
14 with the common rule and the operations of the IRB's
15 and how functional it was to have a system in place
16 that had those elements.
17 So, now, that said, I think all of us in
18 all of our working groups contexts the children's
19 this morning yesterday when we were talking about
20 genetics and families want to think outside of the
21 box and Mary Faith emphasized that at every turn in
22 the road.
667
1 The ethics codes, however, aren t
2 something that have evolved separate and apart from
3 the common rule. And indeed I passed out the
4 American Sociological Association's code of ethics
5 at the last meeting. There s really a synergism
6 between the two.
7 Some of us have studied these documents.
8 We want to go back and restudy to see almost how
9 certain things are articulated where the common rule
10 might not have adequately articulated. So for
11 example recordings in public places seems to be a
12 rub, and how can we better educate from those ethical
13 guidelines to say there are guidelines when you are
14 doing recording in public places to preserve that
15 material.
16 And so I think we will have a lot to say
17 but not because we are going to develop a new set of
18 moral guidelines, although were we to encounter some,
19 I think they would be generically sharable. I don t
20 think this is something that is idiosyncratic to the
21 social and behavioral sciences and that is why I said
22 yesterday that I don t see myself as representing
668
1 those fields of science exclusively. I see myself as
2 knowledgeable about them and what I have to say I
3 hope will have broader applicabilities.
4 CHAIRPERSON MARSHALL: I have Greg. Who
5 else had a -- okay. Abbey and then Jonathan and then
6 I want to open the floor up after that.
7 DR. KOSKI: I just very quickly add that
8 the Belmont Report, the National Commission, actually
9 as the report is entitled and it includes behavioral
10 and biomedical sciences and the fundamental ethical
11 principles that are delineated there I think in fact
12 it is important for everyone to recognize that they
13 do indeed apply across the entire domain of human
14 research.
15 So I think the last thing in the world
16 that we would want to do would be to somehow say that
17 research that is done in the behavioral and social
18 science somehow subscribes to a different set of
19 fundamental ethical standards for research. That
20 would be a serious flaw.
21 So I think indeed our efforts are toward
22 focusing on the many instances misapplication of the
669
1 biomedical model to the social and behavioral
2 sciences realm. We benefit actually in multiple ways
3 from that in that we recognize that the burdens that
4 these processes place in many instances both on
5 investigators and IRBs.
6 Where we are having unnecessary
7 misapplication of provisions that would and basically
8 they don t result in enhanced protections for human
9 subjects, but rather are miss guided attempts to do
10 the right thing often through a lack of appropriate
11 understanding is where we ve gone astray. So I think
12 that this working group will help to focus on those
13 areas where we can productively make our system work,
14 both more efficiently and effectively.
15 CHAIRPERSON MARSHALL: Jonathan.
16 MS. MEYERS: Quickly. The National
17 Bioethics Commission, I haven t heard much mention of
18 it in the last couple of days and I m wondering is
19 there anything among the many reports that they have
20 issued and would apply to this area, so that we don t
21 have to go and reinvent the wheel and start from
22 ground one.
670
1 DR. F. LEVINE: To the extent either
2 because of our shared lack of awareness of some of
3 the social behavioral research it gives some of you
4 the feeling that we are starting from square one. I
5 could not have put better what Greg just said. I
6 don t see us as starting from square one at all and I
7 actually don t see the social and behavioral sciences
8 as a particularly unique challenge. I think some of
9 our complexities raise some important challenges.
10 The NBAC report fully addressed to social
11 and behavioral scientist and I think probably
12 received lots of commentary about those portions of
13 the report that did so just so as it in other areas.
14 A indeed Marjorie Spears who was central to the
15 staffing of that committee is a talented psychologist
16 that was detailed from CDC that is central to social
17 and behavioral scientists at CDC and is an active
18 member of the social and behavioral science research
19 community.
20 I think actually that report even where I
21 may feel with my personal hat on that it hasn t quite
22 hit the boat or maybe missed the boat in certain
671
1 areas. Certainly it didn t miss the boat in being
2 inattentative to the social and behavioral sciences.
3 It certainly sought to address those issues and I
4 think will give us material as it will give this
5 committee material in other areas.
6 DR. MORENO: I actually want to endorse
7 that last point and suggest that not only that
8 report, but also the human biological materials
9 report in the context of the genetic stuff we're
10 doing. We need to have someone come from NBAC and
11 perhaps a principal staffer and do a little briefing
12 on that for us.
13 I think that you re absolutely right about
14 the history, none the less, I have to say when I go
15 up the hill from the medical school to the grounds at
16 UVA and on the few occasions when I m asked to go up
17 there to talk about ethics with my colleagues in
18 behavioral sciences, I sometimes feel the way I did
19 when I walked in a room full of doctors 22 years ago
20 when I started when I started teaching medical
21 ethics. There's at the very least there's less
22 intellectual energy devoted it seems to me
672
1 anecdotally among the rank and file behavioral
2 investigator to ethical issues then even among many
3 of our physician colleagues, several of whom are here
4 who have made such a change in the culture.
5 I'm being a little bit facetious, but I
6 mean to say that I think that the medical world has
7 thought more about these issues than the social
8 science world among the rank and file, not among the
9 leaders perhaps.
10 Having said that and gone out on that limb
11 I also do want to say that my understanding is
12 entirely another matter that our charge is specific
13 with respect to the common rule but that there are
14 some federal agencies that conduct what some people
15 would consider to be behavioral research, at least
16 survey research who are not signatories to the common
17 rule. I guess I'm asking for point a clarification
18 about that. And whether that ought not also to be a
19 part of what, a question at least that we raise as
20 part of this work.
21 DR. F. LEVINE: Survey research
22 methodology is so pervasively used in society that it
673
1 may be that there is an agency that either funds or
2 undertake surveys that may or may not fall under the
3 common rule, but as a method and as a generic set of
4 issues that it raises in terms of ethical guidelines
5 it will be interrogated, I think, in our group so
6 fully and that probably is one of the mature areas of
7 work that I think that that would have a spillover
8 effect even to contexts that aren't under the common
9 rule just as so much of the research currently that
10 isn't a common rule funded project. It is certainly
11 reviewed by local IRBs.
12 DR. KOSKI: Actually, Rachel, I don't know
13 whether or not HUD is actually a signatory to the
14 common rule. You may know, but I guess whether or
15 not it is I would mention that the new charter for
16 the Human Subjects Research Subcommittee as I
17 mentioned in yesterday's discussion has actually been
18 enhanced to include among its members not only the
19 signatories of the common rule but every federal
20 office, department, and agency that's engaged or
21 involved in human research in any way. So that for
22 instance the Social Security Administration has come
674
1 forward as part of that group and then we have an ex
2 officio member here.
3 So we are truly trying to work toward a
4 fully integrated process across all the government
5 agencies.
6 CHAIRPERSON MARSHALL: I'll allow one
7 question for Bob and then I went to open floor for
8 public commentary.
9 DR. R. LEVINE: I won't take the time.
10 CHAIRPERSON MARSHALL: Let me ask if
11 whether there are ex officio members who have
12 questions or comments?
13 DR. ROSE: Susan Rose from the Department
14 of Energy. First of all I am grateful to this
15 committee which I think is very wise and deliberative
16 and I hope from my prospective that we can hide under
17 your wings. So I was also hurt today by the NSF
18 folks bringing the table the fact that there's a lot
19 of science still not on you agendas.
20 I think it came a lot closer today, but
21 there is a huge amount of research that goes beyond
22 or is totally not behavioral and is not biomedical
675
1 and has to follow these rules or else hides from the
2 rules because we can't fit it under the current
3 category, so I have both problems.
4 I think I talked yesterday with Dave
5 Cloughman a little bit at the Department of Justice.
6 They do a lot of work at our sites. A lot of the
7 stuff that I'm talking about is using people to test
8 stuff or a thing or some sort of implement there may
9 be a risk involved. In some cases there's a large
10 risk. It's not a privacy issue, folks obviously know
11 that they're doing whatever it is, if it's a test
12 driver or something like that it's not a secret to
13 them. So I would like to know -- Phil mentioned that
14 the other agencies should be heard from. I would
15 like to know how to go about that.
16 I would also like to say, and I think this
17 is true of the Department of Justice and probably NSF
18 as well as DOE, we do a lot of traditional stuff so
19 I'm only asking for help on the stuff that's not
20 traditional.
21 One of the other things that I think my
22 problem is the sole human subjects person at the
676
1 Department of Energy, at headquarters at any rate,
2 the definition of research leaves me wide open for
3 people who don't want to be research and people who I
4 want to fall under this and don't. So I have two
5 problems, I need help with inclusion, occupational
6 health studies where they claim it's an occupational
7 study and it's not research, and yet they have people
8 from other sites coming in, Boston Med School, for
9 example, and looking at workers 2000 miles away and
10 going into very private medical records.
11 The other kinds of things are these
12 engineering studies where it never crosses an
13 engineer's mind that he's using people and putting
14 them at risk in his human subject research; he's
15 never heard of that. So those are the kinds of
16 things.
17 And then my last issue, and I think I
18 could use this as a weapon, if you guys could help,
19 the issue of science. A lot of these things -- my
20 worst problems are politically motivated studies
21 where there's no -- I could stand on my head I can't
22 find any scientific value. So some addressing at
677
1 least in this committee where the way you weigh that
2 science is going to be a little tougher than in the
3 strictly biomedical research. So any help that you
4 could provide, Phil. Thank you.
5 MR. RUBIN: Let me respond in part because
6 I totally agree with everything that you're saying
7 and it is a real problem and a real issue. A couple
8 of suggestions, then I can talk to you after. First,
9 you can't be reactive, you have to be proactive. One
10 of the things we find out is that at the National
11 Science Foundation people seemed unaware. In the
12 research community not necessarily our program
13 officers but even there you have to be proactive that
14 any time a human being is involved, not even
15 directly, indirectly, after the fact in anyway and in
16 any possible way if there's human there at all,
17 potentially human there's an issue that you have to
18 face and think about seriously.
19 One of the things that we do, and once
20 again, we all operate under limited budgets but we do
21 and we try to do within the constraints we do
22 outreach. You can't just wait till something happens
678
1 you have to go out there in advance. We do outreach
2 both to the research communities by going out and
3 trying to talk to them about these issues and to
4 listen to them about what they are. But also within
5 the foundation we try to meet regularly with program
6 officers because they change frequently and say, do
7 you realize that what you're engaged in involves
8 human beings potentially and, so for example, in
9 engineering, nanotechnology, computer science there
10 used to be less of an awareness.
11 Now at least, every program officer
12 understands this. They complain at the same time
13 that the communities they deal don't. But our
14 response is, well it's your obligation to make it
15 clear, that this is a two-way street. So that is one
16 thing is that that's an issue that's a real one and
17 you have to try to grab it and bring it to you and
18 work with it.
19 I don't want to -- the time is short I
20 would happy to -- and there were in number of
21 questions I'd be happy to discuss additional issues.
22 The other thing is, in terms of the agencies all we
679
1 can do is beg all the agencies in the federal
2 government to take this issue seriously. All of them
3 are involved. There's not one agency that's not
4 involved people, and we cannot force them, the
5 National Science Foundation cannot be a big gorilla
6 either. We don't want to be seen as the way we view
7 the NIH as the big guerrilla; we want to all be co-
8 equal in this thing and try to realize that to
9 participate. So we encourage you to participate. We
10 will work with you and what we are trying to do is
11 actively go out and find people at agencies, if
12 they're not the official person, who are willing to
13 be a part of this enterprise.
14 CHAIRPERSON MARSHALL: Please go ahead and
15 respond and then a I think Greg has a response on
16 point and then I have Bob. You need to be at the
17 microphone because we are -- your words are going
18 down for prosperity.
19 DR. ROSE: Oh great, I m sure they ll love
20 that at DOE.
21 [Laughter.]
22 DR. ROSE: I didn't mean to sound like I
680
1 don't do outreach in education. That's probably what
2 I spend 85 percent of my life doing and I would feel
3 terrible if you don't have copies of our educational
4 materials. That's the most important thing I do but,
5 nonetheless, the areas I mentioned wouldn't have to
6 be a continual fight if you guys could help produce
7 some guidance. That's all I'm saying.
8 I would like to help but I need to know
9 how. Well, sitting on a behavioral and social
10 science committee isn't going to help me, that's my
11 only --
12 DR. KOSKI: First of all, I would like to
13 recognize that Susan Rose is actually the one who has
14 picked up the ball to leave the effort to create a
15 federal-wide handbook for human research as one of
16 the projects of the human subject research
17 subcommittee.
18 But to the specific point that she raises,
19 how do we get there. Well, in fact, I think that the
20 800-pound gorilla here could be indeed the human
21 subjects research subcommittee. I frequently talk
22 about that as sort of the awakening of a sleeping
681
1 giant because it has that capability, but it may need
2 in fact to have the additional recognition and
3 support that would come from appropriate testimony
4 before Congress with respect to the need to have all
5 of the federal agencies stepping up to the plate and
6 exercising their responsibilities in this area.
7 That's an opportunity that also coming.
8 CHAIRPERSON MARSHALL: Bob, and please
9 stay at the microphone.
10 AUDIENCE PARTICIPANT: I'm a member of the
11 public, I don't want to get lost in the shuffle here.
12 CHAIRPERSON MARSHALL: Please just stay
13 there and we will -- I've got Bob and then the floor
14 is yours.
15 DR. R. LEVINE: On the topic that Susan
16 was talking about there have been other agencies that
17 have gotten started on this. I think one that has
18 interest very much in common with social behavioral
19 sciences is CDC. I was chair of their committee to
20 evaluate and make recommendations on their human
21 subjects protection system and one of the big issues
22 that came up was so many of their activities used
682
1 devices that are indistinguishable from research as
2 they do their outbreak investigation their
3 surveillance and things of this sort. And we came up
4 with a set of recommendations that might have some
5 value for your group since they do overlap.
6 Another area where there's been a lot of
7 issues is in the area of evaluating public benefit
8 programs. And what happened in the 1980s is that the
9 common rule adopted an exclusion or an exemption for
10 public benefit -- evaluation to public benefits
11 programs and this exemption has been used over and
12 over again in the programs that are most prominently
13 evaluating new approaches to Aid For Dependent
14 Children.
15 The recommendation of my group to CDC was
16 that they should stop trying to define research so
17 that it fits exactly what they want it to regulate.
18 But what they should do instead it identify some
19 categories of activity that are either clearly
20 research or that look enough like research so that
21 somebody raises the issue and go the exemption route.
22 The rationale for developing exemption for
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1 evaluation of public benefits programs could apply
2 equally to doing such things as outbreak
3 investigation and so on.
4 If you want to see that report you'll be
5 able to see the line of reasoning that went into it.
6 Thank you.
7 DR. F. LEVINE: I think we all would like
8 to see that report. When I referred to field
9 experiments I was thinking about some of the large-
10 scale evaluations when in my conversations with Susan
11 I think she's talking about a band of testing that
12 may or may not, and is as much not than is social and
13 behavioral science research and how that falls within
14 a system. I think that one -- Greg s very helpful
15 starting point meaning the subcommittee on human
16 subject research protection is a starting point.
17 I think her additional question is, how
18 does that graft into our process. But perhaps by
19 starting there by getting different agencies together
20 that have that articulated interest that doesn't
21 neatly fit into biomedical sciences health sciences,
22 social and behavioral sciences as they intersect with
684
1 health or other phenomena, if you could sketch out
2 something, perhaps in a working memoranda, then it
3 may be that some of us who empathize with the falling
4 between multiple stools of science if there is no one
5 left to fall within could help articulate where that
6 fits and whether that fits this or whether that fits
7 something else.
8 And I could tell from your e-mail and from
9 our conversation that you knew you had an issue that
10 involves humans but that it wasn't classically within
11 a research regulatory regime.
12 CHAIRPERSON MARSHALL: Thank you. Please
13 tell us who you are.
14 DR. NOBLE: Hi. My name is Jack Noble
15 I'm a professor at Catholic University. I'm on
16 sabbatical this year doing a study of human subjects
17 protection and I have not had IRB review of my
18 project even though my sabbatical has been approved
19 by the university including the Provost. Isn't that
20 interesting?
21 Am I investigator reporter? Am I a spy?
22 You know, systematically documenting the -- and
685
1 reporting systematic deception or opportunities?
2 There are any number of very interesting questions
3 that I have asked myself as I went off on this little
4 sabbatical. But here I would like to ask you to
5 consider an issue from a look at your process and
6 what you are about the from a political economic
7 standpoint.
8 Obviously you are a part of a very large
9 and expanding marketplace wherein there are
10 transactions, wherein things of value are exchanged,
11 subject are exchanging their lives and increased
12 risks in exchange for something that they view may
13 benefit them.
14 Now, the subject of public accountability
15 has come up. And, you know, as I view the process
16 and how far this goes I think public accountability
17 and gets very difficult for an industry. In fact the
18 only way you could do it right would perhaps be like
19 Swift's suggestion to the starving Irish that they
20 eat their own children.
21 I don't think that will happen. It's too
22 horrendous. So in that circumstance I don't think
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1 you're going to get much public accountability unless
2 you have some sort of an external system that is
3 automatically in place.
4 Now, where does this leave me? It leads
5 me to the suggestion that might be considered by this
6 whole advisory committee of putting in place some way
7 of compensating those individuals who suffer death,
8 injuries, or illnesses that arise out of and in the
9 course of participation in research. That has been
10 suggested by one of the earlier national advisory
11 commission's bioethics advisory commission it was not
12 implemented. But it gives an opportunity to deal
13 with the risky business that researchers involve
14 human subjects in.
15 The definition of condition, I listened to
16 very carefully, includes a situation where an
17 individual becomes involved in a piece of research.
18 And how do you deal with those injuries and illnesses
19 that happened in the course of participation. Well,
20 justice would require that there be some level of
21 compensation or indemnification, no-fault, good
22 people make mistakes. The estimation of risk is
687
1 wrong. But somebody pays the price and it's not the
2 investigator it is that human subject.
3 So if you had -- you want to know about
4 adverse events, you want to know where they occur and
5 with what frequency and how bad they are, look at the
6 dollar costs of compensating deaths, injuries,
7 disabilities, and the echogenic illnesses. The
8 insurance industry is quite capable with its large
9 sets of actuarials plus a mechanism, certainly all
10 those workers' compensation carries, would be able to
11 carry policies very well and if they're not willing
12 to carry a policy for an institution based upon risk
13 rating the Office of Human Research Protection would
14 not have to come to the rescue.
15 The marketplace would define what is an
16 unacceptable financial risk for it to continue to
17 provide coverage for that type of practice. So I
18 just throw this out, it's a little bit out of the box
19 but not too far. It's only as far as workers'
20 compensation for injuries -- accident and injuries
21 that arise out of and in the course of employment.
22 And the last statement, most of your
688
1 subjects are more like employees than volunteers if
2 you really look at it. They provide a service. Now,
3 I don't want to get into the analogy too far because
4 those services of children are prescribed by child
5 labor laws with some very small exceptions. So let's
6 not carry that analogy too far, all examples limp.
7 This is one that limps right at that point. But I
8 just throw this out. Consider it and maybe it will
9 help you a little bit.
10 CHAIRPERSON MARSHALL: Thank you very
11 much. You have raised an issue that I think is dear
12 to all of us and it is something that we will have on
13 our agenda at some point. So thank you. And I think
14 Abbey also would like to speak to your remarks.
15 MS. MEYERS: I don't think the risk of
16 injury has been a major thing in the past. Back in
17 1989 we had a National Commission on Orphan Diseases
18 and at that time we said to the drug industry you're
19 just not stepping up to plate on pediatric drug.
20 You're not testing them, you're not labeling your
21 drugs for pediatric uses. And the industry defended
22 itself by saying the liability issue is so big we
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1 don't want to test drugs on children.
2 So we did a search on some legal databases
3 to find out how many lawsuits there had been for
4 investigational drugs, whether in adults or children
5 and we found only one case in the whole country. And
6 that case, the case was a malpractice case against
7 the physician because he didn't adequately tell the
8 patient that she was in a trial and it was not
9 against the company that manufactured whatever
10 product was being tested.
11 So as time went on of course we see a lot
12 of pediatric research on drugs now and liability
13 doesn't seem to be a problem, but I think that in
14 cases where patients felt that they were harmed they
15 felt that this was, in most cases, a risk they took
16 when they signed the informed consent document. That
17 informed consent document does a lot to tell people I
18 accepted the risk and very few cases have come to
19 court.
20 MS. MEYERS: Thank you, Abbey. I have
21 Bob.
22 DR. R. LEVINE: We have examples of
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1 attempts to set up no-fault compensation programs.
2 The University of Washington at Seattle ran such a
3 program for eight years. The total amount of money
4 they paid out without contesting any claims -- the
5 total amount of money they paid out was under
6 $10,000. The biggest claim was $1,500 from a normal
7 volunteer who fainted while blood was being drawn and
8 struck his teeth on the radiator.
9 We have one other example. There are many
10 examples. I'm only going to mention one more. When
11 John Arnold set up his so-called "alternate subject
12 population program" in Kansas City he had normal
13 volunteers enrolling in one Phase I drug study after
14 another, and after a while he decided that he wanted
15 to have workers compensation for his employees just
16 as he had for the other employees in the building,
17 and he brought in a real insurance company who
18 studied the books and came out with a premium workers
19 compensation for phase one subjects that was very
20 slightly higher than it was for the secretaries in
21 the office there.
22 Now, about 20 years Pat Patello of Harvard
691
1 wrote me a letter saying, why are they trying to make
2 behavioral research look like that very dangerous
3 biomedical research? He said do you have any data on
4 the dangers of biomedical research? And I sent him
5 the Arnold story among others. And a couple of days
6 later I got a handwritten note on yellow paper
7 saying, "I had no idea. I fired my secretary and
8 it's for her own good don't you know."
9 CHAIRPERSON MARSHALL: Please, tell us who
10 you are.
11 MR. CLOUGHMAN: Hello, my name is Dave
12 Cloughman, I'm from the National Institute of Justice
13 and I guess the social science group we do a lot of
14 research in the area of criminology and Sally is
15 serving on the panel, I think that's great. A couple
16 of things that I would encourage the panel to
17 consider, and Phil and I have talked about this. One
18 is, I think at some point the social sciences you
19 come out with almost like a good laboratory practice
20 document that basically lays out that types of
21 studies they do, the types of risk that run the gamut
22 from no risk to some number of X risk; how those are
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1 handled, and what types of issues there are. And I
2 think the big issue is going to be confidentiality
3 and breaches of confidentiality is where I think the
4 major risk lie in most of these studies.
5 And that brings up a couple of issues for
6 me. One, at the Department of Justice we have a
7 confidentiality regulation that applies to all
8 research we sponsor. Actually it's under the omnibus
9 of crime control access not all of Justice but it's
10 the National Institute of Justice and it's much more
11 restrictive than the certificate of confidentiality
12 that people know under the Public Health Service Act.
13 And that raises some problems with investigators and
14 IRBs that don't understand those restrictions and we
15 are working at educating them on that. It also
16 raises some conflicts with mandatory reporting issues
17 such as child abuse, domestic violence, et cetera.
18 But on the other hand the confidentiality
19 rule that we have has allowed me to stick my nose
20 under the tent, so to speak on some technology
21 development areas where you wouldn't define them as
22 human subject research under Part 46, but because we
693
1 have the confidentiality rule and require
2 notification I can ask the investigators to make sure
3 that people understand the risk of the studies that
4 they are involved in. And there's things like
5 technology development and law enforcement areas.
6 There's some advantages in that as well as
7 shortcomings. Thank you.
8 CHAIRPERSON MARSHALL: Thank you very
9 much.
10 DR. F. LEVINE: I think that s in an area
11 compatible with your language is a topic we will
12 interrogate thoroughly.
13 [Laughter.]
14 CHAIRPERSON MARSHALL: Felice and Phil,
15 thank you very much. We know that you truly are just
16 beginning, so we look forward to hearing from you in
17 the future.
18 [Applause.]
19 CHAIRPERSON MARSHALL: We have about half
20 an hour left and I do want to talk about some
21 housekeeping things relative to our working and
22 moving forward as a committee. I think probably I am
694
1 not going to recap or review recommendations that
2 were already at least done this morning in terms of
3 what we did yesterday in lieu of time. I may just
4 touch on children and social science.
5 But I want to have us as a committee to
6 talk about how some issues that I would like for us
7 to think on, some issues that have arisen yesterday
8 and today in terms of how we proceed doing our work.
9 So I have a list. I want to start with, I am going
10 to save the composition of our workgroups and put
11 that a little bit further down the list because I
12 know there's going to be discussion on that.
13 So there are a couple of things I would
14 just like to move forward with before that, and they
15 are these: One of them is that we have ex officio
16 members from I believe from 25 agencies appointed to
17 this committee. Obviously not all of you are in
18 attendance.
19 [Laughter.]
20 CHAIRPERSON MARSHALL: But I want to
21 emphasize the fact that we need our ex officio
22 members here, we want them here, they should be a
695
1 working and an integral part of our committee. You
2 do comprise our committee in a very fundamental way.
3 So I'm putting the message out there gently in the
4 form of a call but also an expectation. And my
5 expectation is this, the ex officio members will
6 attend this meeting or they will send a designee from
7 each of the agencies that are delineated in our
8 charter.
9 We by the rules of our charter are
10 required to have a majority of our ex officio members
11 just as we are required to have a majority of our
12 committee members in order to convene and have a
13 meeting. So here is the expectation. Our meetings
14 begin at 8:30. They end at least when they are
15 formally supposed to end according to our schedule.
16 I think in the future we will have a
17 second layer of tables with names microphones and so
18 forth so that it is easier for our members to
19 participate, or ex officio members, so the call is
20 out there the expectation is that every agency will
21 have a representative here at our meeting. And I
22 look forward to that and fruitful participation.
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1 The second has to do with our own
2 committee, and I hope you take this in a constructive
3 spirit. I know that each of you wears not just one
4 and not just two, but many hats and that you have
5 professional lives and personal lives and you have
6 graciously given up time out of both of those to be a
7 member of this committee.
8 I would ask that in the future -- I know
9 that our first two meetings have been scheduled so
10 that you're teaching schedules and other events in
11 your lives were already done before you were even
12 appointed to this committee but we are working very
13 hard to plan our schedule far enough in advance that
14 you can, I hope, work your professional life, you're
15 teaching schedules, around our committee meetings.
16 And I don't want to be unrealistic or
17 unfair in terms of expectations, but we will meet
18 quarterly and I truly would urge you to be here both
19 days, the full day, for all of our meetings because
20 we need each and every one of you. So I hope that
21 you can do that and that if I can help intervene with
22 deans or whomever, if that needs to be for you to be
697
1 here, then I will be happy to do that.
2 And my second piece of encouragement is
3 that we hear from each and every one of you at this
4 meeting. And I know that not all of us as an
5 expertise in research ethics, per se, none of us is
6 certainly Bob Levine who has the breadth of knowledge
7 and experience in this area that I think probably as
8 a group none of us could surpass if we put our
9 collective brains together we still wouldn't reach up
10 to the mark that Bob has.
11 But you're here for a reason and I need to
12 have active meaningful participation from each of
13 you. So if you're feeling unfamiliar with an area,
14 read the background materials. We will try and get
15 them to you in a more timely fashion in the future.
16 So that is a call, a plea, an expectation
17 for active meaningful participation from each member
18 of this committee, don't be shy there's no reason to
19 be.
20 I want to talk about resources. Again,
21 our committee was begun at the end of a former
22 administration. It happened rather quickly. We live
698
1 for the moment within the constraints that were
2 originally set out, but as those of you who were at
3 the research summit that occurred recently now I made
4 the statement that I am going to assume that the
5 resources are there that we need to do our job. And
6 I'm going to do more than assume that. We are going
7 to work very hard with the new administration now
8 that the hiring freeze has been lifted and some of
9 the constraints that Greg and his office and Kate
10 have been under are lifted to make sure that we have
11 the resources that we need both the fiscal, the
12 financial resources to convene working groups and to
13 have consultants and to have papers written by
14 scholars and authorities that we need to have done.
15 Those will happen.
16 So I want you to know that we're aware
17 that we have been constrained and that Kate Louise
18 Gottfried has been working 22 hours a day, seven days
19 a week for a long time and that needs to change. She
20 needs to have staff assistance. We as a committee
21 need to have the resources we need to do our job.
22 And I think Greg has put it well also, in the past,
699
1 and is an ardent advocate for that.
2 So I'm going to assume the resources are
3 there and I'm going to make sure that the resources
4 of there.
5 I want us to think a little bit about the
6 regulations. I've mentioned this before. Within the
7 various working groups it has become clear that we
8 may want to consider or we may identify an area where
9 the common rule, where the regulations may need
10 clarification, explication, or where we may even want
11 to make a recommendation that they be changed.
12 So I would like for us, as a committee, to
13 be thinking about the fact that that moment in time
14 may come, and whether we want to do it on a piecemeal
15 basis or whether at some point in time we want to
16 make a large, more wholesale recommendation, but I
17 would ask that each workgroup chair, and all members
18 of the workgroup, as you're doing your work, if there
19 is a component of your work that has to do with the
20 regulations and a recommendation that may bear on
21 changing the regulations in the future, that you
22 bring that to our attention so that we at least have
700
1 all of those nicely explicated as we move along in
2 the process.
3 I would also ask you, as a committee, to
4 be thinking about the best process for advising that
5 the regulations might be changed if any of you comes
6 to that consensus in your work.
7 Yes, Abbey?
8 MS. MEYERS: It covers 17 agencies; right?
9 So if we want to change regulations, it would have to
10 be approved by 17 agencies; right?
11 CHAIRPERSON MARSHALL: Absolutely. And
12 remember, we are an advisory group only. So what I'm
13 asking is, within the purview of our work, if we were
14 to recommend to any of the folks to whom we advise,
15 in our charge, our charter, that we would make that
16 recommendation. Yes, changing rulemkaing, lawmaking,
17 you know, there's an established procedure which Greg
18 can speak to. Certainly others have alluded to it,
19 whether they're in fear of it, or in support of it.
20 But we don't make regulations, we don't
21 set policy, but we do make recommendations, and we
22 can make recommendations to change the regulations if
701
1 we see fit.
2 So I just want you to bear that in mind
3 because there's a current that underlies probably
4 almost each working group that we've had so far that
5 may result in that sort of recommendation, or has the
6 possibility for resulting in it.
7 Yes, Susan.
8 MS. KORNETSKY: In line with that, I think
9 it would be helpful in the working group, I mean,
10 obviously a change in the regulations, I understand
11 and I appreciate that we can do that. But I sort of
12 look at things as long term and short term and things
13 that are pressing. And so in our working groups, I
14 think that if there is something that's pressing, we
15 may have to tackle it from two points. And I think
16 -- because, if there is something pressing, changing
17 the regulations is not going to happen that quickly.
18 CHAIRPERSON MARSHALL: Well said, and you
19 made that point earlier. We do need to think about
20 plan A and also be thinking -- looking forward to
21 plan B. So I agree with you wholeheartedly.
22 I have Kate and then Elliot.
702
1 DR. KIRSCHSTEIN: Indeed, that's how we
2 have been proceeding with all the workgroups and
3 we've had a two-tiered sort of process where we deal
4 with the immediate and then the long term. And I
5 think all of the working groups will end up doing
6 that because of that fact, that regulation revision
7 if it's required would take a while.
8 CHAIRPERSON MARSHALL: I just don't want
9 us to lose sight of the long term if it's there. So
10 thank you very much, Susan.
11 Elliot.
12 DR. DORFF: Just in terms of the first
13 things we were talking about in terms of scheduling.
14 I understand July 30th and 31st is our next meeting.
15 Have our meetings for the rest of the year been
16 scheduled or not?
17 DR. KIRSCHSTEIN: No, because the
18 committee members have not been able to supply us
19 with their available data for the forthcoming
20 meetings. But we are -- what we may do, because we
21 had wanted to schedule them all in advance is just
22 start scheduling them and have you put them on your
703
1 calendars.
2 My concern, though, is that I really want
3 to have, you know, as much representation as
4 possible. And so I'm a little hesitant to go ahead,
5 but we'll do that and then see what happens.
6 CHAIRPERSON MARSHALL: It sounds as though
7 the committee is saying, please go ahead and
8 schedule. Okay.
9 All right. And, again, if we can help you
10 in any way. Obviously this is my biased perspective,
11 but I'm not sure that any of us is engaged in
12 anything that is more important than the charge to
13 this committee which is ensuring the protection of
14 human research subjects.
15 Let me ask, in terms of workgroups, we
16 talked about them earlier today, and we are
17 establishing our own mechanisms. There's nothing
18 that's been handed to us in terms of you will do it
19 this way. So, we are discovering these mechanisms or
20 creating them as we go along. It's vitally
21 important, I think, as I said yesterday and at our
22 first meeting that our process be excellent, that it
704
1 be exemplary. Because the outcome of our work
2 depends wholly on the excellence of our process. And
3 we have made a promise that we will work in a
4 transparent way and in a inclusive way. And that is
5 and will be how we work.
6 So let me ask, we began the conversation
7 within the last two days with the workgroup on
8 financial relationships. Whether the way that we
9 have outlined that working group's work to proceed
10 fits well with you, whether you have suggestions for
11 changing how we're going to proceed, and just to
12 remind you, there is a document -- a draft document
13 that has been presented to the committee as a whole.
14 We have had input on that today.
15 It is -- or if it's not already, will be
16 on our web site for further comment from ex officio
17 members, from members of the public, from committee
18 membership who may not have had the chance to weigh
19 in today, or yesterday, there will be a revision
20 incorporating those remarks that will subsequently be
21 put on the web with, again, a chance for comment --
22 open comment before what we hope is a penultimate
705
1 draft will come back to the committee as a whole.
2 Working groups do not have final products.
3 Our committee has a final product.
4 So does that seem like a good procedure to
5 you? Obviously I'm aware that a different working
6 group may need to work in a different way, but I'm
7 asking whether this seems fair and transparent in
8 terms of our goals?
9 DR. FLEISCHMAN: I would recommend that
10 each of the working groups identify their products as
11 from the working groups.
12 CHAIRPERSON MARSHALL: Thank you. Thank
13 you.
14 We did have a little -- it was unfortunate
15 that the report from the financial relationships
16 group came as a letter. Kate and I actually tried to
17 have that. When we thought that we had had those
18 first and last pages removed because they looked like
19 a fait accompli and they didn't smell right and so I
20 was rather dismayed to see that wonderful piece of
21 work come in the form that it did. So in the future
22 I will say now, the rule is that working groups are
706
1 bringing products and that the product should have no
2 -- in no way imply that they are a fait accompli.
3 Alan and then Bob.
4 DR. FLEISCHMAN: And might I suggest, if
5 that document -- is it on the web site at this point?
6 If it is not, we might wish to change that language
7 so that we can give everyone who reads it the
8 understanding that it's a product of a working group.
9 This committee, I'm not suggesting that it's not a
10 wonderful product. I mean, this committee may bless
11 it and not change a word, and all we'll have to do
12 then is to change working group to NHRPAC. But I
13 think it would be helpful for the public to view it
14 as a work in progress.
15 CHAIRPERSON MARSHALL: Yes, it has to be
16 that way. Kate.
17 DR. KIRSCHSTEIN: It's just if you note
18 what's in your notebook, that's the way it should
19 appear on the web site, and that's what we had
20 intended. That was the first draft. If you look at
21 the first draft that's in the notebook, it's a
22 different format than what you got as a revision.
707
1 DR. FLEISCHMAN: But it still says NHRPAC.
2 At least the thing I read.
3 DR. KIRSCHSTEIN: It says, "To NHRPAC
4 Committee Members from the working group."
5 DR. FLEISCHMAN: No, I understand that.
6 But the document --
7 DR. KIRSCHSTEIN: Oh, okay, got you. I
8 understand.
9 DR. FLEISCHMAN: -- assumes NHRPAC has
10 approved it.
11 DR. KIRSCHSTEIN: No, I understand.
12 DR. FLEISCHMAN: And that's quite
13 confusing to the not-so-naive reader.
14 DR. KIRSCHSTEIN: Yes, I agree. Right.
15 We'll take care of that.
16 CHAIRPERSON MARSHALL: Thank you, Alan.
17 DR. R. LEVINE: My comments address to the
18 same point. My belief is that the working group that
19 Marc headed was trying to do us a service by drafting
20 language for our signature. And I was going to
21 propose that if it is going to go on the web site in
22 its current form, that there be that explanatory lead
708
1 in that this is drafted as if it came from NHRPAC,
2 but it hasn't yet.
3 CHAIRPERSON MARSHALL: Adil and then
4 Felice.
5 DR. SHAMOO: Do I understand you correctly
6 that the working group procedure is not going to
7 change, for example, we do teleconferencing, et
8 cetera, et cetera, and then the working group meeting
9 is private, not open to the public. And my thinking
10 is that really the working groups are working as a
11 subcommittee. I'm very familiar with NBAC because I
12 attended a lot of their meetings. We were a part of
13 the NBAC "groupies" they're called.
14 The subcommittees met. A lot of people
15 from the committee, even though they are not members
16 of that subcommittee attended the meeting,
17 participated in the discussion, and they have the
18 same material. And here we don't have that
19 opportunity. We don't have the material, we don't
20 know when they meet, and the public definitely does
21 not have any access to the deliberations.
22 The important thing is accountability and
709
1 deliberation and both now are lacking. The working
2 group, as I understood from Kate, is collect
3 information. And none of the working group so far I
4 have seen is really purely collecting information,
5 rather they were trying to develop a product. So
6 they are really functioning as a subcommittee. So
7 it's up to the committee and you, Mary Faith, to
8 decide that. But my thinking is that we should
9 consider making at least when we have in person
10 working group that the meeting is open to whoever
11 want to attend that meeting.
12 CHAIRPERSON MARSHALL: I think that's a
13 good suggestion. We talked about it a little bit,
14 you know, we do need mechanism to put words on paper.
15 But that's a good suggestion. That if a working
16 group convenes, you know, physically in a place that
17 that is advertised and that it's open to whomever
18 would like to attend. So we will ensure that in the
19 future that happens.
20 And I do hope that in terms of access that
21 we are fair in that regard also. These meetings are
22 public. The public has the opportunity, you know,
710
1 via the e-mail to comment on any product. So I
2 recognize that letting all members of the public know
3 that they have access is a problem. And I do
4 remember at the first meeting asking that if there
5 are any suggestions and certainly asking advocates
6 and professional associations -- advocacy
7 associations to please put the word out, let your
8 membership know via whatever communication mechanism
9 you have what our web site is and that anyone is
10 invited to weigh in.
11 And if there are further suggestions in
12 terms of the way we can get the word out, please let
13 us know.
14 Greg.
15 DR. KOSKI: Again, Kate is the expert on
16 this, but this committee obviously as a federal
17 advisory committee is governed by the requirements of
18 the FACA, you know, Act, or the Federal Advisory
19 Committee Act. There are provisions within that act,
20 as I understand it, for working groups that are not
21 open public meetings. They're certainly nothing
22 secret or that's non-transparent or in any way
711
1 deceptive about the working group structure as it has
2 been used to this point. After all, every single
3 piece that comes back from any of them is openly
4 discussed clearly before this group.
5 And I would urge that the committee retain
6 the option for utilizing working groups in an
7 appropriate manner so as to not encumber the progress
8 of the group, recognizing that the principal and the
9 goal has been so clearly delineated, not only by the
10 members, but by the chair is to have an open, robust,
11 and inclusive process. So, don't cut off your nose
12 to spite your face.
13 CHAIRPERSON MARSHALL: Felice?
14 DR. F. LEVINE: Let me just comment that
15 I, of course, share the common view that's emerged
16 that when we put the financial relationships report
17 up that I'll say we should go with the one that's in
18 the book. But I think in that spirit, I think with
19 the informed consent of that working group, I that
20 cover memo will need to be shifted because it still
21 sounds like it's the first paragraph of the letter.
22 But I think working groups are different
712
1 from subcommittees. As I said in December,
2 biographically, I sit on the Secretary of Commerce's
3 Decennial Census Advisory Committee and we have
4 working groups extremely productively to do leg work.
5 But I think all of us are now articulating and
6 reaffirming that it's a subvehicle of getting stuff
7 to this group as things go back and forth and
8 ultimately what is owned is owned by this group.
9 In that context, when we have had meetings
10 in and around our Decennial Advisory Committee which
11 also meets more or less quarterly and if there's a
12 scheduled time for working groups, you know, anybody
13 can sort of sit in who might like, but obviously
14 because a lot is done by conference call and other
15 vehicles that while the products are transparent and
16 widely disseminated, and the whole notion of these
17 groups is to bring input from wide audiences, I think
18 there is a role for that leg work that just couldn't
19 happen as a committee as a whole. And I think that's
20 why FACA permits that to happen that way.
21 CHAIRPERSON MARSHALL: Thank you Felice.
22 I think that just to clarify that in the
713
1 future that if our working groups are physically
2 getting together in a geographical location, we will
3 make that known ahead of time so that whoever would
4 like to attend that can attend.
5 Abbey, I also wanted to just speak to your
6 concern about proportionality or the ratio of perhaps
7 public members isn't the right term -- but I want to
8 make sure that your concerns are adequately spoken
9 to. I do have a note from Marc who says, "I think
10 that Abbey is right. The Committee should" -- he
11 says, "consent to any appointment of a noncommittee
12 member to a committee working group." And I'm not
13 sure whether that's what you were getting at, so
14 could you just clarify so that I'm clear about the
15 point that you wanted to make?
16 MS. MEYERS: It is proportionality because
17 there should be more members of this committee on any
18 subcommittee than there are members of the public.
19 And we should be sure that it's evenly balanced so
20 that the people on the committee, if we're talking
21 about regulations, that pediatricians are going to
22 have to abide by in the future, we should not have
714
1 100 percent pediatricians on that committee. Because
2 they're not going to vote to regulate themselves.
3 CHAIRPERSON MARSHALL: Thank you. Do you
4 feel as though what we've talked about today in terms
5 of process and procedure adequate addresses those?
6 We certainly can put on our web site the composition
7 of any committee. Do you think that as we are
8 convening initially our committees that we need to
9 get that information to the full committee to consent
10 to in terms of what the group looks like?
11 MS. MEYERS: The way this committee is
12 right now, it looks like we have four committee
13 members and 11 non-committee members on the
14 committee.
15 CHAIRPERSON MARSHALL: But remember that I
16 consider our ex officio members as members. I mean,
17 we can't convene a meeting by our charter without the
18 majority of them present. So are you considering
19 them in a different light than I am?
20 MS. MEYERS: I don't know. What's the
21 number of the government liaison?
22 CHAIRPERSON MARSHALL: I think we have 25
715
1 -- 22, thank you. Twenty-two ex officio -- 22
2 agencies that are represented.
3 MS. MEYERS: Okay. This subcommittee
4 doesn't have 22 ex officio members on the
5 subcommittee?
6 CHAIRPERSON MARSHALL: No, but are you
7 asking that every working group be sort of a small
8 duplication in terms of proportionality? I mean, I
9 think that we need to be fair that we have the
10 expertise and the voices of those who should be at
11 the table, at the table. And that's my primary
12 concern rather than direct proportionality, is that
13 everyone who should have a voice is there.
14 MS. MEYERS: Yes.
15 CHAIRPERSON MARSHALL: Then we don't laeve
16 people out. That's my big worry. I don't want
17 someone who wants to be at the table not to be at the
18 table.
19 MS. MEYERS: I'm afraid to say, but the
20 members of this committee should be increased on that
21 committee so that more people -- and I'm not
22 volunteering for it, because they already -- they got
716
1 me for another one.
2 CHAIRPERSON MARSHALL: I had Greg, and
3 then Denyse, and then Adil, and Alan. And you've got
4 about four minutes. You each have a minute.
5 DR. KOSKI: I have to take issue with the
6 assertion, Abbey, that pediatricians couldn't vote to
7 regulate themselves in a sense. I'm sorry, I think
8 it's an important point and I don't mean to quibble
9 here, but the important point is to have the
10 necessary expertise and the thoughtful -- you know,
11 the wisdom, the collective wisdom of the people
12 there. Indeed to adopt the position that because one
13 happens to care for children one is incapable of
14 putting the interest of the children somehow ahead of
15 their -- I think it makes a statement that I don't
16 think you intended to make.
17 You know, these working groups are not
18 voting groups, or anything. These are groups that
19 are working toward a product that comes back to this
20 committee. And, indeed, there are numerous examples.
21 In fact, you know, many of the regulations and all
22 there are things that the scientific community have
717
1 developed in consult with the public and others,
2 emphasis specifically for the purposes of regulating
3 themselves and recognize the value there.
4 So, again, I don't mean to quibble, but I
5 think it does a disservice to the dedicated members
6 of a variety of communities if we somehow impugn
7 their reputations or their judgments saying that they
8 wouldn't be able to act in a responsible manner.
9 CHAIRPERSON MARSHALL: Kate.
10 DR. KIRSCHSTEIN: I don't want to belabor
11 this, but I just want to indicate that both from a
12 philosophical and a logistical perspective, I agree
13 with what Greg is saying. But in particular, from a
14 practical perspective, again, we had 17 members of
15 the committee. You can't have many more than five
16 committee members on each workgroup. It's just not
17 feasible.
18 And the issue is, I think, I'd love to
19 talk with you more about this independently. But the
20 issue is, do we have, as Greg said, adequate
21 representation with respect to the issue we're
22 addressing and do we have a reflection of the public
718
1 of say consumer person as we did, we looked for one,
2 two and three consumer type people for the workgroup
3 and diversity as well. And I think that's what you
4 really are getting towards is the issue of balance
5 and objectivity. And that's what we've been striving
6 for and I think we should continue to do so.
7 CHAIRPERSON MARSHALL: Denyse.
8 DR. THORNLEY-BROWN: [Bad mic.] I
9 basically wanted to say two things. We don't need to
10 be worshiping at the altar of numbers. Ultimately
11 the product -- important and that's the thing that we
12 all bring to the table. So we have this product --
13 CHAIRPERSON MARSHALL: Thank you. Adil.
14 DR. SHAMOO: Well, I was the one who
15 brought the assent issue. Regardless of what the
16 composition is, I think the committee should -- there
17 should have been a proposal. Here is the
18 composition. Here are the members, and I said, most
19 likelihood we will give the nod for it. But that
20 hasn't happened and I think that was missing. And it
21 still is missing. To be very honest these working
22 groups were appointed by a process where the
719
1 committee had no ownership in them.
2 CHAIRPERSON MARSHALL: If I'm remembering
3 the process, I asked at the last meeting people who
4 are interested and those sort of were the people who
5 ended up on the committee, I hope, and then we, as
6 Kate said, tried to balance it in terms of looking
7 for outside expertise. But, what we will do in the
8 future, Adil, is for the members of the committee, we
9 will post the names of those who have been appointed
10 to working group and ask that via the e-mail or a
11 call to Kate, or whatever, if you have -- you want to
12 register a concern about the composition of the
13 committee that you let us know. How does that sound?
14 DR. SHAMOO: Well, I have mentioned to
15 you, I would like to see Vera Sharov be in the
16 children's group. She has worked for two years
17 studying that issue and I think she has an input.
18 And I think the committee really does not have
19 someone like her with her point of view on the
20 committee and I think she should be.
21 CHAIRPERSON MARSHALL: Thank you, Adil.
22 And Alan, you were next on the list.
720
1 DR. FLEISCHMAN: I just wanted to give us
2 some evidence here. The committee consisted of the
3 executive director who both was participant and staff
4 of NHRPAC. Five NHRPAC members, three
5 representatives of ex officio groups, one public
6 advocate, and six academic pediatricians representing
7 different expertise ranging from neonatology to
8 public policy to infectious diseases to diversity and
9 adolescent issues in mental health.
10 So, the actual mechanisms of having
11 thought about those six members, had to do with the
12 recommendations to the Secretary from the Congress
13 about the kinds of pediatricians that ought to be
14 considered in helping to analyze the regulations.
15 And, in fact, that was part of the conversations that
16 we had in trying to put together this committee so
17 that we could fulfills some of the obligations that
18 were part of the request. And I certainly felt that
19 those different types of pediatric scientists and
20 ethicists were important -- you know, gave us
21 different groups.
22 And, then finally, the American Academy of
721
1 Pediatrics has a bioethics committee. Skip Nelson
2 happens to, I think, chair it at the moment. And
3 they have been -- not anymore. He just shifted and I
4 haven't been on it for a few years.
5 That bioethics committee tries to create
6 ethical guidelines for the practice of pediatricians
7 and is dramatically criticized by pediatricians for
8 being overly concerned with ethical regulatory
9 structures. So it isn't that pediatricians haven't
10 had that role previously in trying to regulate their
11 own practices.
12 CHAIRPERSON MARSHALL: Thank you very
13 much. And we need to wind down. We don't have a
14 quorum anymore. And I'm sorry people have had to
15 drift off.
16 Alan, thank you very much for your work in
17 chairing the pediatrics group. And I would like to
18 thank each and every one of you for being here and
19 for your work during the interim. And I look forward
20 to hearing from you soon on our work products and to
21 seeing you at our next meeting.
22 Thank you all.
722
1 [Whereupon, at 4:35 p.m., the meeting was
2 adjourned.]
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